SEARCH

SEARCH BY CITATION

Keywords:

  • homeostasis;
  • phosphatases;
  • phosphorylation;
  • T cell

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. T cell homeostasis
  5. PTPs regulating T cell survival and homeostatic proliferation
  6. Additional PTPs potentially implicated in CD8 T cell homeostasis
  7. Co-ordinating phosphatase activity in T cells
  8. Concluding remarks
  9. Acknowledgements
  10. References

A complex network of signalling events coordinate the differentiation, activation and maintenance of T lymphocytes. Tyrosine phosphorylation and dephosphorylation by protein tyrosine kinases and protein tyrosine phosphatases (PTPs) respectively, are critical for the activation and propagation of these signalling cascades. Intriguingly, the removal of tyrosyl phosphate moieties from phosphorylated proteins by phosphatases can contribute to both the positive and negative regulation of signalling events. The complex and diverse roles of individual PTP family members in immune cells is evident by the range of immune disorders caused by PTP deficiencies. Central to several such immune disorders is the disturbance of T cell homeostasis, as characterized by aberrant cell growth, survival and activation. The survival and homeostatic proliferation of naïve and memory CD8 T cells is primarily regulated by signalling events downstream of the T cell receptor complex and common γ chain cytokine receptors, events frequently targeted by PTP activity. We review the primary PTPs involved in CD8 T cell homeostasis, focusing on the signalling nodes that they target. In addition, because the mechanisms that co-ordinate PTP activity are only partially understood, we discuss currently proposed models of regulation and highlight unanswered questions.


Abbreviations
Csk

C-terminal Src kinase

HEPTP

haematopoiesis-specific PTP

IL

interleukin

JAK

Janus kinase

LYP

lymphoid tyrosine phosphatase

MHC

major histocompatibility complex

MKP

mitogen-activated protein kinase phosphatase

PEP

PEST domain-enriched tyrosine phosphatase

PTP

protein tyrosine phosphatase

SFK

Src-family kinase

SHP-1

SH2 domain-containing PTP-1

SHP-2

SH2 domain-containing PTP-2

STAT

signal transducer and activator of transcription

TC-PTP

T cell PTP

TCR

T cell receptor

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. T cell homeostasis
  5. PTPs regulating T cell survival and homeostatic proliferation
  6. Additional PTPs potentially implicated in CD8 T cell homeostasis
  7. Co-ordinating phosphatase activity in T cells
  8. Concluding remarks
  9. Acknowledgements
  10. References

T cell homeostasis is maintained by a network of signalling cascades activated in response to environmental cues, including cytokine and antigen availability. The modulation of protein tyrosine phosphorylation by protein tyrosine kinases and protein tyrosine phosphatases (PTPs) is one of the most critical post-translation modifications required for the propagation and modulation of signal transduction. The depletion or deregulation of PTP activity can cause inappropriate T cell proliferation, survival and activation, thereby contributing to inflammation, autoimmunity and leukaemogenesis. The present review discusses the variety of mechanisms by which PTPs contribute to the survival and homeostatic proliferation of naïve and memory CD8 T cells. In addition, unresolved questions regarding the co-ordination of PTP activity in T cells are highlighted.

T cell homeostasis

  1. Top of page
  2. Abstract
  3. Introduction
  4. T cell homeostasis
  5. PTPs regulating T cell survival and homeostatic proliferation
  6. Additional PTPs potentially implicated in CD8 T cell homeostasis
  7. Co-ordinating phosphatase activity in T cells
  8. Concluding remarks
  9. Acknowledgements
  10. References

Homeostasis ensures that the size of the peripheral T cell population does not exceed the available physical space within the microenvironment and that the T cell repertoire remains sufficiently diverse to provide protection against an array of environmental pathogens. Accordingly, the majority of antigen-specific T cells expanded over the course of an infection are eliminated following pathogen clearance, returning the peripheral T cell population to an appropriate size and diversity [1–3].

The peripheral T cell population is not limited to naïve T cells. The small fraction of cells that survive the contraction phase following pathogen clearance are maintained as memory T cells, which respond more robustly upon secondary infection.

Despite differences in antigenic experience, T cell receptor (TCR) threshold and metabolic state, the signalling pathways that control naïve and memory CD8 T cell survival and homeostatic proliferation overlap considerably. Although both naïve and memory CD8 T cells rely on signalling downstream of common γ chain cytokine receptors, only naïve T cells require the activation of the TCR complex through engagement with self-major histocompatibility complex (MHC) complexes [4].

TCR-mediated signal transduction and CD8 T cell maintenance

Selection in the thymus ensures the deletion of T cells that overtly recognize self-MHC complexes. Nevertheless, the surviving T cell population that is exported to the periphery retains reactivity against low avidity self-MHC complexes [4]. The requirement for such interactions for naïve T cell survival and homeostatic proliferation has been controversial given that the original experimental models relied on lymphopenic hosts [5,6]. However, the development of models in which naïve CD4 or CD8 T cells are transferred into non-lymphopenic MHC-deficient hosts confirmed previous assertions that naïve T cell survival requires TCR–self-MHC interactions [4,7,8].

Most recently, it has been reported that the scanning of dendritic cells by T cells, in the absence of foreign antigen, results in the continuous recognition of self-MHC complexes by the TCR. Such interactions were found to be required to maintain basal TCR signalling because depletion of dendritic cells led to a 40% reduction in the phosphorylation of the TCRζ chain [9].

The nature of signalling events elicited by TCR–self-MHC interactions has been difficult to characterize, although parallels are evident to those events initiated following T cell activation. In both contexts, protein tyrosine phosphorylation is required to initiate and propagate signalling events. The Src-family kinases (SFKs), Lck and Fyn, are the primary kinases responsible for the basal levels of TCRζ phosphorylation, which mediates recruitment of the Zap-70 kinase. Inducible deletion of Lck in Fyn-deficient mice, as well as the subsequent loss of TCRζ phosphorylation, shortened the life span of naïve T cells, providing indirect evidence that TCR-mediated signalling is required for their survival [9a]. Mechanistically, it has been hypothesized that TCR-mediated tonic signalling maintains a required gene expression profile in naïve peripheral T cells, although this model has not been fully validated.

Memory CD8 T cells were originally considered to be similarly dependent on TCR stimulation for their survival. Several models proposed that the presentation of residual antigen within the host is required to maintain memory T cells. Such models were proven to be incorrect however, and the persistence of memory T cells is now accepted to be independent of foreign antigen or self-MHC [10–12]. Rather, it is cytokine availability that has been identified as the critical determining factor in the maintenance of memory T cells [4,13–17].

Signalling downstream of the cytokine receptors in CD8 T cell maintenance

Although required, tickling of the TCR complex through interactions with self-MHC is not sufficient for the survival of naïve CD8 T cells. Signalling downstream of common γ chain cytokine receptors is also essential [18]. For example, the transfer of naïve T cells into an interleukin (IL)-7 deficient host results in limited cell survival [19,20]. Moreover, the administration of neutralizing anti-IL-7 sera equally compromises T cell survival [14,21].

Cytokines are differentially required by naïve and memory T cells. IL-7 is the primary cytokine driving naïve T cell survival, whereas alternative cytokines such as IL-15 play a limited role. By contrast, both IL-7 and IL-15 are required for memory T cell survival. This dual requirement has been extensively studied in mice deficient in either IL-7, IL-15 or their respective receptors [22–24]. The findings suggest that, although IL-7 is required for cell viability, IL-15 supports homeostatic proliferation.

One of the primary pathways downstream of the common γ chain receptors is the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway. Cytokine binding results in receptor dimerization, allowing for the juxtaposition and subsequent cross-phosphorylation of associated JAK molecules. Activated JAK molecules are then responsible for the phosphorylation of downstream targets, including STAT molecules. Tyrosine phosphorylated STAT molecules dimerize and translocate to the nucleus, where they promote the expression of genes implicated in cell survival and proliferation [25,26].

An intact γ chain receptor–JAK–STAT signalling axis is required for the maintenance of both naïve and memory T cell populations. Indeed, deletion of either the common γ chain receptor, or constitutively associated JAK3, results in both human and murine severe combined immunodeficiency [27,28]. Similarly, simultaneous deletion of STAT5a and STAT5b, the primary STAT family members downstream of common γ chain receptors, abrogates CD8+ T cell survival [29]. Conversely, activating mutations in JAK and STAT molecules contribute to tumourigenesis. For example, constitutively active JAK2 is associated with acute lymphoblastic leukaemia, whereas JAK1 and JAK3 are implicated in T-cell precursor acute lymphoblastic leukaemia [30–32]. Similarly, transgenic expression of STAT5 results in lymphomagenesis as a consequence of CD8+ T cell expansion [33,34].

Because the JAK–STAT signalling axis downstream of cytokine receptors is initiated and propagated by reversible tyrosine phosphorylation events, it is not unexpected that PTPs have proven to be critical modulators of JAK–STAT signalling. Intriguingly however, examples of PTPs that both positively and negatively regulate JAK–STAT signalling have been reported.

PTPs regulating T cell survival and homeostatic proliferation

  1. Top of page
  2. Abstract
  3. Introduction
  4. T cell homeostasis
  5. PTPs regulating T cell survival and homeostatic proliferation
  6. Additional PTPs potentially implicated in CD8 T cell homeostasis
  7. Co-ordinating phosphatase activity in T cells
  8. Concluding remarks
  9. Acknowledgements
  10. References

The identified 107 PTPs are subdivided into four distinct classes bases on their structural and biochemical properties. A conserved signature motif (XHCSXGXGRXG) containing a catalytic oxidation-sensitive active cysteine residue is characteristic of Class I–III. The conserved cysteine residue executes a nucleophilic attack on substrate tyrosine residues. The largest class is Class I, which includes 38 classical PTPs that target phosphorylated tyrosine residues and 61 dual-specific phosphatases that target phosphorylated tyrosine, serine and threonine residues. By contrast, Class II includes a single PTP, namely low molecular weight PTP, whereas Class III comprises the three cell cycle Cdc25 regulatory proteins. Finally, Class IV is a family of four aspartate-based PTPs implicated in cell death [35].

To date, it is the classical PTPs of Class I that have been most extensively studied in the context of T cell physiology (Fig. 1). The classical PTPs are further subdivided into two groups, which are both expressed in T cells: the receptor-type PTPs and the nonreceptor PTPs. Receptor-type PTPs include an extracellular domain and a single transmembrane domain followed by a cytoplasmic tail, which contains either single or tandem catalytic domains. Cytoplasmic PTPs contain a single catalytic domain that is flanked by amino- and carboxyl terminal protein-binding motifs serving both regulatory and targeting roles.

image

Figure 1.  Contribution of PTPs to CD8 T cell homeostasis. A schematic representation of CD8 T cell differentiation during immune activation or homeostatic proliferation. Stages negatively (red) or positively (blue) regulated by PTPs are shown and described. The minor proportion of total PTPs indicated highlights our limited understanding of the role of PTPs in CD8 T cell homeostasis. A systematic evaluation of all PTPs in physiologically relatable models is required.

Download figure to PowerPoint

Multiple receptor and nonreceptor PTPs are expressed preferentially in the haematopoietic system. CD45, nonreceptor SH2 domain-containing PTP-1 (SHP-1) and PEST domain-enriched tyrosine phosphatase (PEP) are expressed at elevated levels in immune cells where they modulate signalling events unique to immune cells, such as those downstream of immunoglobulin receptors. However, such PTPs are not sufficient. Additional ubiquitously expressed PTPs, such as PTP-PEST, also play essential roles in T cell homeostasis (Fig. 1).

In the present review, PTPs with varying expression patterns, specificities and subcellular localizations are discussed with regard to their role in maintaining peripheral T cells in a resting quiescent state. In addition, reference is made to the immunological defects associated with the disruption of PTP activity in each case.

CD45

The transmembrane PTP CD45 is expressed on the surface of all haematopoietic lineages, during development and activation [36], and has been proposed as the primary regulator of membrane proximal tyrosine phosphorylation events in lymphocytes. The critical role of CD45 is made evident in mice harbouring a single point mutation that inactivates the CD45 inhibitory wedge responsible for CD45 dimerization and inactivation, leading to severe autoimmune nephritis [37].

The generation of CD45-deficient mouse models helped to identify the regulatory role of CD45 in TCR-mediated signalling during T cell development and activation [38–40]. Characterization of the mechanism by which CD45 regulates TCR-mediated signalling has been complicated by the observation that CD45 dephosphorylates both the positive and negative regulating tyrosine residues in Lck. Specifically, in dephosphorylating the negative regulatory tyrosine residue 505 (Y-505), CD45 releases Lck from an inhibitory intramolecular conformation. However, CD45 is also capable of dephosphorylating the positive regulatory tyrosine autophosphorylation site (Y-394) within the kinase domain, resulting in diminished kinase activity [41–43]. As discussed below, CD45 has been proposed to act as a sensitive rheostat that sets the TCR threshold of activation by modulating Lck phosphorylation, Lck activity and the initiation of TCR-mediated signalling.

The expression of CD45 in alternate haematopoietic lineages, as well as in immature B and T cells before surface expression of antigen receptors, suggested an additional role for CD45 in haematopoiesis and the existence of unidentified substrates. Yeast two-hybrid screening identified JAK1, JAK2, JAK3 and Tyk2 as CD45 binding partners and substrates in vitro. Moreover, disruption of the cd45 gene resulted in enhanced cytokine receptor signalling [44]. CD45 deficient bone-marrow-derived mast cell lines hyper-phosphorylate JAK2, STAT3 and STAT5 in response to IL-3 stimulation, whereas CD45−/− pro-B cells exhibit enhanced induced activation of JAK1 and STAT5 signalling in the presence of IL-7. Similarly, JAK1 phosphorylation is augmented in CD45−/− thymocyte following IFN-α stimulation [44].

The mechanism by which CD45 modulates JAK activation has not been fully characterized. Two hypothesis have been proposed that are not mutually exclusive. The first would suggest that the negative regulatory role of CD45 results solely from binding and dephosphorylating conserved tyrosine residues within the activation loops of JAK1, JAK2 and Tyk2. However, Dok-1 has been identified as an additional CD45 binding partner and substrate. Because overexpression of Dok-1 in T cells results in reduced JAK and STAT phosphorylation in response to IL-3 and IFN-α stimulation, it has been proposed that CD45 modulates JAK–STAT signalling through this interaction [45].

The physiological importance of CD45 in cytokine signalling remains unclear. CD45 deficient mice do not exhibit any striking cytokine hyper-activation phenotype. This was suggested to be a consequence of the extensive redundancy in the negative regulation of JAK signalling in lymphocytes. It is quite plausible that, in the absence of CD45, suppressor of cytokine signalling proteins, as well as SHP-1 and SH2 domain-containing PTP-2 (SHP-2), are sufficient to maintain JAK–STAT signalling within an appropriate range [46]. Nevertheless, the mutation of CD45 in multiple leukaemias and lymphomas has been interpreted as evidence that CD45 does indeed play a role in maintaining lymphocyte homeostasis through the negative regulation of cell growth in response to cytokines [47].

SHP-1

Similar to CD45, SHP-1 is predominantly expressed in the haematopoietic system and has proven to be critical for maintaining resting peripheral T cells. Both SHP-1, and the structurally related SHP-2, contain a single phosphatase domain that is flanked by two SH2 domains dictating their subcellular localization and mediating their interactions with substrates [48]. Under basal conditions, the N-terminal SH2 domain is wedged within the phosphatase domain in an auto-inhibitory conformation, which is released upon stimulation or an elevated concentration of available high-affinity substrate. Proteomic approaches have identified the differential specificity of the SH2 domains of SHP-1 and SHP-2. Each SH2 domain within each SHP protein shows both unique and redundant specificities that are determined by adjacent consensus sequences [48–53].

SHP-1 expression is essential for the development and maintenance of the haematopoietic system. SHP-1 null mice exhibit a variety of immune disorders that ultimately result in death by 2–3 weeks of age. Reported immune defects include hyper-proliferation and elevated activation of granulocytes and macrophages, in addition to autoimmunity [54–56].

Although SHP-1 acts as a negative regulator of signalling downstream of antigen, cytokine and growth factor receptors, it is its role in establishing the threshold activation in resting peripheral T cells that is critical for inhibiting T cell activation in response to self-antigens [48,57]. To do so, SHP-1 is involved in a negative-feedback loop that attenuates TCR signalling following stimulation. Specifically, following stimulation of the TCR, SHP-1 is phosphorylated and activated by Lck. Activated SHP-1 is then recruited to the TCR complex and dephosphorylates molecules associated with the complex, including Lck itself, Zap-70, PI3K and Vav [58–64]. Originally, such a mechanism appeared to be self-limiting. Further evidence, however, has confirmed that the role of SHP-1 in the negative regulation of TCR signalling is essential for the discrimination between self and nonself antigens. Strongly-binding antigens produce high and prolonged Erk activation that phosphorylates Lck and causes a conformational change rendering Lck resistant to dephosphorylation by SHP-1. By contrast, stimulation by weakly-binding antigens results in transient Erk activation that is insufficient to promote SHP-1 resistant Lck. This mechanism ensures that T cells do not respond to low-affinity self-antigens. Rather, in response to such antigens, Lck is dephosphorylated by SHP-1 and further TCR signalling events are extinguished [65].

The described model suggests that SHP-1 activity is determined by the strength of TCR signalling. A T cell specific SHP-1−/− TCR transgenic mouse permitted the quantification of peptide required for the activation of SHP-1-deficient CD8 T cells. Indeed, peptide doses of ten- to 100-fold less are required to activate SHP-1−/− CD8 T cells compared to controls [57]. Moreover, CD8 T cells exhibit a proliferative and survival advantage in the absence of SHP-1 following stimulation, whereas the effector functions are unaltered. Strikingly, although CD8 SHP-1−/− short-lived effector cells are expanded in vivo, they are not resistant to cell death and do not survive the contraction phase. Thus, SHP-1- deficiency enhances the primary CD8 response but does not alter the size of long-lived memory populations [66]. These observations suggest that alternative PTPs are critical for the generation and maintenance of memory T cells.

SHP-2

The characterization of SHP-2 in the T cell lineage was originally hampered by the embryonic lethality of the SHP-2−/− mouse [67]. Nevertheless, alternative complementary mouse models of SHP-2 deficiency have established the role of SHP-2 in T cell physiology. First, complementation of recombination activating gene-2 deficient blastocyts with SHP-2-deficient embryonic stem cells did not result in the differentiation of any T lineage cells in generated chimeric mice. SHP-2 was shown to negatively regulate c-kit receptor signalling, which is required for early haematopoiesis and lymphopoiesis [68,69]. Thus, the absence of T lineages in this system may reflect the role of SHP-2 in haematopoietic progenitor cells. Second, a T-cell specific SHP-2-deficient mouse model allowed for the assessment of the T cell-intrinsic effects of a SHP-2 deficiency. In alternate cell types, SHP-2 can both positively and negatively regulate JAK-STAT signalling [70]. In T cells, however, the role of SHP-2 in JAK-STAT signalling remains unclear. Rather, SHP-2 has been found to be required to activate signalling downstream of the TCR receptor complex. The absence of SHP-2 partially blocked T cell development and led to a dramatic decrease in the number of peripheral T cells. Although the survival of SHP-2-deficient T cells was not affected, the proliferation in response to TCR stimulation was stunted [68]. Thus, it remains to be clarified whether SHP-2 is required for basal TCR signalling initiated by interaction with self-MHC to maintain T cell numbers.

Lyp/PEPand PTP-PEST

The human lymphoid tyrosine phosphatase (LYP) and the murine orthologue PEP are also required to establish the threshold of TCR signalling and to maintain naïve T cell quiescence. Human LYP variants that decrease protein expression, or disturb LYP-based protein complexes, are associated with several autoimmunity diseases, such as type I diabetes, rheumatoid arthritis and myasthenia [71–75]. Similarly, PEP-deficiency in a genetically susceptible mouse background results in hyper-responsive B cells, elevated auto-antibody levels and the development of a lupus-like disease [76].

The mechanism by which Lyp/PEP negatively regulates the activation of T cells and inhibits autoimmune reactions has been proposed to act through its negative regulation of basal TCR signalling. A large fraction of total cellular PEP (20–50%) is associated with C-terminal Src kinase (Csk) [77], an inhibitor of Src-related protein tyrosine kinases. While Csk phosphorylates the negative regulating tyrosine of Lck, PEP dephosphorylates the activating tyrosine residue (Y-394) of Lck [78–80]. As such, the Csk–PEP complex acts synergistically to suppress Lck activity.

Intriguingly, PEP is not required for the regulation of TCR signalling in all T cell subsets. PEP deficient mice exhibit enhanced positive selection in the thymus, whereas negative selection is unaffected. The number of peripheral naïve T cells is unaltered in young mice, indicating that the regulatory mechanisms controlling the size of the peripheral T cells population are intact. Moreover, as cellular expansion, cytokine production and calcium mobilization following TCR stimulation are comparable between wild-type and PEP−/− T cells, immediate T cell activation appears to be unaffected. The subsequent expansion and differentiation of effector T cells in the absence of PEP, however, is increased. In addition, upon ageing, PEP-deficient mice develop splenomegaly and lymphadenopathy on a C57BL/6 genetic background. This pathology correlates with an accelerated accumulation of CD44HIGHCD62Llo memory-phenotype CD4 and CD8 T cells, which suggests a disruption of memory T cell homeostasis [81].

By contrast, the closely-related phosphatase PTP-PEST is dispensable for memory T cell homeostasis. The absolute number of memory T cells is unchanged in the PTP-PEST knockout mouse. Rather, PTP-PEST plays a positive regulatory role in the re-activation of memory cells upon secondary antigen exposure [82]. Similar to PEP, PTP-PEST interacts with Csk and is targeted to lipid rafts. However, PTP-PEST also interacts with a significant number of additional substrates, one of which may contribute to T cell homoaggregation. Because homoaggregation is required for re-activation during a secondary response, the lost capacity of PTP-PEST−/− memory T cells to form homoaggregates may be responsible for the promotion of T cell anergy and the reduced susceptibility to autoimmunity observed in PTP-PEST deficient mice [82]. Thus, although Lyp/PEP plays negative regulatory role in the expansion of effector/memory T cells, PTP-PEST plays a positive regulatory role in memory re-activation. The contrasting roles of these related PTPs highlight the complexity of PTP function in T cell physiology, which goes beyond simply opposing kinase activity.

T cell PTP (TC-PTP)

The phosphatases discussed thus far act predominantly within the cytoplasm, targeting membrane proximal molecules. However, PTPs residing in the nucleus are equally critical for the regulation of signalling networks. TC-PTP is one such PTP.

TC-PTP is a nonreceptor classical PTP expressed ubiquitously, although the highest levels of expression are detected in haematopoietic cells. Alternative splicing generates two TC-PTP isoforms that are differentially localized. Although both isoforms contain a classical phosphatase domain at the N-terminus, the minor 48-kDa isoform includes an endoplasmic reticulum retention sequence, whereas the major 45-kDa isoform contains a nuclear localization signal at the C-terminus. The nuclear localization of the major 45-kDa isoform is dynamic, with the cytoplasm fraction enlarging upon cellular stress [83]. In the nucleus, TC-PTP dephosphorylates STAT molecules and, consequently, contributes to the negative regulation of their activity [84,85]. The existence of additional nuclear TC-PTP targets has yet to be reported.

Despite being born healthy, TC-PTP-deficient mice succumb to anaemia and progressive systemic inflammatory disease within 3–5 weeks of age. The coincident elevation of systemic IFN-γ levels and the expansion of a hyper-sensitive macrophage population contributes to the overproduction of inflammatory mediators. Consequently, a progressive infiltration of mononuclear cells into non-lymphoid tissues occurs and leads to tissue damage [86].

In contrast to the enlarged splenic macrophage population, the B cell lineage is repressed in the absence of TC-PTP. Elevated secretion of IFN-γ by the bone marrow stroma contributes to a block in early B cell development, which correlates with a reduction in the absolute number of peripheral B cells [87]. Thus, the splenomegaly characteristic of TC-PTP-deficient mice is not a consequence of hyper-proliferating B cells but rather results from extramedullary erythropoiesis and the accumulation of erythroblasts in the spleen.

The role of TC-PTP in T cell homeostasis has proven difficult to dissect given the gross inflammatory disease and early lethality of TC-PTP deficient mice. Phenotypic analysis of the T cell compartments of TC-PTP−/− mice before the onset of disease detected comparable numbers of peripheral CD4 and CD8 cells in control and TC-PTP−/− mice [86]. However, peripheral T cells purified from TC-PTP−/− mice have a defective proliferative response to anti-CD3 stimulation ex vivo. Gr-1+ myeloid cells in the spleen of TC-PTP−/− mice secrete elevated levels of IFN-γ and nitric oxide, which inhibit T cell responses [88]. The continuous exposure of TC-PTP−/− CD4 and CD8 cells to such factors could possibly result in cellular exhaustion, rendering the T cells unresponsive.

The recent generation of a T cell specific TC-PTP-deficient mouse has allowed for the separation of the intrinsic and extrinsic effects of TC-PTP deletion on T cells. In the T cell condition TC-PTP knockout mouse, an accumulation of CD4 and CD8 memory-phenotype T cells (CD44HIGHCD62LLO) is evident in the spleen, lymph nodes and liver. The enhanced generation of memory-phenotype T cells most likely reflects the role of TC-PTP in the negative regulation of SFK downstream of the TCR complex resulting in the lowering of the threshold for T cell activation. Enhanced activation of signalling pathways downstream of the TCR complex was associated with an increased proliferation response upon antigenic stimulation both in vitro and in vivo. Such responses correlate with the reported increased in susceptibility to inflammation and autoimmunity observed in T cell specific TC-PTP-deficient mice [89].

The role of TC-PTP is not one-dimensional because SFKs are only one of multiple TC-PTP substrates. In T cells, TC-PTP mediated dephosphorylation of JAK1 and JAK3 is associated with the elevated activation of STAT1 and STAT5 in response to IFN-γ or IL-2 stimulation observed in TC-PTP−/− T cells [90]. Because closely-related PTPs such as PTP-1B fail to bind JAK1 and JAK3, we would suggest that TC-PTP is the primary PTP responsible for the negative regulation of signalling downstream of common γ chain cytokine receptors in haematopoietic cells.

As further evidence of the important regulatory role of TC-PTP in cytokine signalling, depletion of TC-PTP enhances the cytokine sensitivity of T-ALL cells. Knockdown of TC-PTP, in both ex vivo mouse primary T-cell leukaemia cells and human T-ALL cell lines, results in elevated and prolonged JAK1 and STAT5 phosphorylation in response to IL-7. It has been proposed that depletion of TC-PTP heightens cytokine sensitivity, thereby providing leukaemic cells with a proliferative advantage in the presence of limited cytokine concentrations [91]. Despite these findings, the role of TC-PTP in the regulation of naïve T cell proliferation in response to cytokine availability within distinct peripheral microenvironments has not been tested.

Additional PTPs potentially implicated in CD8 T cell homeostasis

  1. Top of page
  2. Abstract
  3. Introduction
  4. T cell homeostasis
  5. PTPs regulating T cell survival and homeostatic proliferation
  6. Additional PTPs potentially implicated in CD8 T cell homeostasis
  7. Co-ordinating phosphatase activity in T cells
  8. Concluding remarks
  9. Acknowledgements
  10. References

Expression of PTP family members in CD8 T cells is not restricted to those discussed in the present review. To date, more than 40 PTPs have been identified in lymphocytes, although the expression of all family members has not been determined. It is therefore likely that additional family members will be found to contribute to the regulation of naïve and memory CD8 T cell survival and proliferation.

Murine knockout models have been generated for PTPs such as haematopoiesis-specific PTP (HEPTP) and PTPN3. Despite evidence that these PTPs modulate TCR signalling, they proved to be dispensable for T cell biology. Thus, although HEPTP is a negative regulator of mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 and p38 activity in T lymphocytes, HEPTP deficient mice do not exhibit any defect in the distribution or activation of peripheral T cells [92–96]. Similarly, PTPN3 is associated with the plasma membrane actin network and negatively regulates TCR signalling in part by dephosphorylating the TCRζ chain [97] but PTPN3 deficient primary T cells do not display enhanced T cell responses, nor do deficient mice exhibit any propensity for autoimmunity [98]. It is important to consider that compensatory mechanisms, such as the down-regulation of PTP targets, may mask any potential defects associated with PTP depletion.

The role mitogen-activated protein kinase phosphatases (MKPs) in directing T cell fate decisions has also begun to be dissected. Both MKP-1 and MKP-5 have been shown to regulate T cell activation and effector function in vivo [99,100]. More recently, it has been reported that MKP-1 expression in dendritic cells modulates cytokine receptor signalling, as well as cytokine receptor expression, thereby influencing T helper cell differentiation [101]. It remains unknown whether MKPs are required for the survival of memory T cells, however this is a question that should be addressed given the dependence of memory cells on cytokine signalling.

Although only a portion of PTP family members have been examined in detail for their function in T cell development, activation and homeostasis, the increasing number of anti-PTP short hairpin RNA library screens will soon provide the tools required to assess systematically the entire gene family for its function in T cell homeostasis.

Co-ordinating phosphatase activity in T cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. T cell homeostasis
  5. PTPs regulating T cell survival and homeostatic proliferation
  6. Additional PTPs potentially implicated in CD8 T cell homeostasis
  7. Co-ordinating phosphatase activity in T cells
  8. Concluding remarks
  9. Acknowledgements
  10. References

The capacity of CD45, SHP-1 and Lyp/PEP to dephosphorylate Lck and modulate the TCR threshold of activation highlights the overlapping functions of PTPs in T cells. Intriguingly, these PTPs are not interchangeable in T cell physiology given the immune dysfunction observed in the individual PTP knockout mice. Moreover, it should be noted that, to our knowledge, there are no instances where the depletion of one PTP can be compensated for by increased expression of another family member.

The unique immunophenotype of the individual PTP knockout mice, despite a certain degree of redundancy among PTP substrates in vitro, may be a consequence of the multiple mechanisms regulating PTP specificity in vivo. PTP specificity is determined co-operatively by substrate binding, subcellular localization and cellular maturation.

Interactions between PTPs and their substrates are mediated by consensus sequences present in both the catalytic and noncatalytic domains. Although the catalytic domain is conserved among PTP, in vivo PTP domains display a high specificity independent of activity. For example, mutations that render the catalytic domain inactive do not hinder substrate binding [102]. Rather, it is the structure and charge surrounding the catalytic pocket that dictates specificity. In addition, adjacent protein or lipid binding domains and motifs enhance the efficiency of the interactions. For example, the association of PTP-PEST and its substrate Cas is mediated by the poly-proline motif within PTP-PEST and the Cas SH3 domain, in addition to the PTP-PEST catalytic domain. The high specificity of this interaction is the result of both modes of interaction [103].

A secondary advantage of simultaneous binding through both the catalytic and noncatalytic domains is the capacity of PTPs with highly homologous catalytic domains to engage in differential substrate binding. In particular, TC-PTP and PTP-1B share 74% sequence homology within the catalytic domain and yet each targets a distinct set of substrates. Although deletion of either protein affects cytokine signalling in a variety of cell types and both are expressed in the T cell lineage, only TC-PTP binds JAK1 and JAK3 in T cells in response to IL-2 stimulation [104]. The unique regions within the carboxyl terminals of TC-PTP and PTP-1B include multiple tyrosine residues and poly-proline rich regions that support the formation of higher-order protein complexes most likely contributing to substrate specificity.

Subcellular targeting of PTPs accords an additional layer of regulation. With respect to TC-PTP and PTP-1B, the localization of TC-PTP to the nucleus and cytoplasm, as well as the retention of PTP-1B to the cytoplasmic side of the endoplasmic reticulum membrane, dictates substrate availability [104]. Similarly, inclusion versus exclusion from lipid rafts in the plasma membrane plays a role in directing PTP activity. For example, the 5% of CD45 molecules residing in lipid rafts under basal conditions is excluded upon ligation of the TCR complex [105]. By contrast, 20–30% of SHP-1 molecules are constitutively localized to lipid rafts [106]. This differential localization correlates with the role of each PTP in regulating Lck activity downstream of the TCR receptor. CD45 regulates basal signalling downstream of the TCR complex and primes Lck for the phosphorylation of the CD3 cytoplasmic domains and Zap-70 [107]. In comparison, SHP-1 is involved in a negative-feedback loop that terminates TCR signalling following agonist stimulation and T cell activation [65].

The role of differential PTP expression in T cell subsets remains unclear but intriguing. The levels of CD45 expression are progressively increased throughout development, modulating the threshold for TCR signalling [108]. Thus, developing thymocytes express lower levels of CD45, which promotes the dephosphorylation of Y-505, thereby activating Lck and heightening TCR sensitivity during positive selection. By contrast, peripheral naïve T cells express at least twofold higher levels of CD45, which ensures the dephosphorylation of Y-394 and limits basal TCR signalling in naïve T cells to prevent inappropriate T cell activation and autoimmunity [108,109]. However, the level of protein expression does not necessarily correspond to PTP enzymatic activity, especially for the receptor PTPs, which have been proposed to be inhibited by dimerization.

The limitation of PTP activity to specific stages of development as a consequence of differential PTP expression may be over simplistic. Both Lyp/PEP and PTP-PEST are expressed in both naïve and memory T cells. However, PEP and PTP-PEST are dispensable for naïve T cell homeostasis but are required for effector/memory cell expansion and memory T cell re-activation, respectively [81,82]. It has been suggested that the restricted usage of PTPs in memory cells is dependent on the expression of binding partners unique to memory T cells. Currently, no evidence supports or challenges this hypothesis. Alternatively, the dependence of memory cells on particular PTPs may reflect the contribution of certain PTPs to cellular events unique in memory T cell physiology. As such, the dependence of memory T cell reactivation on PTP-PEST has been suggested to be a consequence of the role of PTP-PEST in the formation of T cell homoaggregates, which may prove to be more critical during memory recall responses [82].

Concluding remarks

  1. Top of page
  2. Abstract
  3. Introduction
  4. T cell homeostasis
  5. PTPs regulating T cell survival and homeostatic proliferation
  6. Additional PTPs potentially implicated in CD8 T cell homeostasis
  7. Co-ordinating phosphatase activity in T cells
  8. Concluding remarks
  9. Acknowledgements
  10. References

Extensive cross-talk between signalling pathways downstream of antigen and cytokine receptors occurs to maintain homeostasis. It has therefore proved difficult to identify the role of PTPs in T cell homeostasis and to be able to decipher those signalling pathways that are directly targeted by a given PTP, as opposed to those regulated by PTP substrates. The identification of more PTP binding partners and substrates in T cells will be key to clarifying the many remaining questions. In doing so, however, it will be critical to distinguish between PTP–substrate interactions and PTP-containing protein complexes formed in response to differing stimuli during each stage of development and activation.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. T cell homeostasis
  5. PTPs regulating T cell survival and homeostatic proliferation
  6. Additional PTPs potentially implicated in CD8 T cell homeostasis
  7. Co-ordinating phosphatase activity in T cells
  8. Concluding remarks
  9. Acknowledgements
  10. References

We thank Ms Stéphanie Bussières-Marmen for critical reading and commentary. This work was supported by a grant awarded from the Canadian Cancer Society Research Institute. M.L.T is a holder of the Jeanne and Jean-Louis Lévesque Chair in Cancer Research. K.A.P is a recipient of a postdoctoral fellowship from the Richard and Edith Strauss Foundation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. T cell homeostasis
  5. PTPs regulating T cell survival and homeostatic proliferation
  6. Additional PTPs potentially implicated in CD8 T cell homeostasis
  7. Co-ordinating phosphatase activity in T cells
  8. Concluding remarks
  9. Acknowledgements
  10. References
  • 1
    Jameson SC (2002) Maintaining the norm: T-cell homeostasis. Nat Rev Immunol2, 547556.
  • 2
    Murali-Krishna K, Altman JD, Suresh M, Sourdive DJ, Zajac AJ, Miller JD, Slansky J & Ahmed R (1998) Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity8, 177187.
  • 3
    Blattman JN, Antia R, Sourdive DJ, Wang X, Kaech SM, Murali-Krishna K, Altman JD & Ahmed R (2002) Estimating the precursor frequency of naive antigen-specific CD8 T cells. J Exp Med195, 657664.
  • 4
    Surh CD & Sprent J (2008) Homeostasis of naive and memory T cells. Immunity29, 848862.
  • 5
    Takeda S, Rodewald HR, Arakawa H, Bluethmann H & Shimizu T (1996) MHC class II molecules are not required for survival of newly generated CD4+ T cells, but affect their long-term life span. Immunity5, 217228.
  • 6
    Rooke R, Waltzinger C, Benoist C & Mathis D (1997) Targeted complementation of MHC class II deficiency by intrathymic delivery of recombinant adenoviruses. Immunity7, 123134.
  • 7
    Moses CT, Thorstenson KM, Jameson SC & Khoruts A (2003) Competition for self ligands restrains homeostatic proliferation of naive CD4 T cells. Proc Natl Acad Sci USA100, 11851190.
  • 8
    Hataye J, Moon JJ, Khoruts A, Reilly C & Jenkins MK (2006) Naive and memory CD4+ T cell survival controlled by clonal abundance. Science312, 114116.
  • 9
    Hochweller K, Wabnitz GH, Samstag Y, Suffner J, Hammerling GJ & Garbi N (2010) Dendritic cells control T cell tonic signaling required for responsiveness to foreign antigen. Proc Natl Acad Sci USA107, 59315936.
  • 9a
    Seddon B & Zamoyska R (2002) TCR signals mediated by SRC family kinases are essential for the survival of naive T cells. J Immuno169, 29973005.
  • 10
    Murali-Krishna K, Lau LL, Sambhara S, Lemonnier F, Altman J & Ahmed R (1999) Persistence of memory CD8 T cells in MHC class I-deficient mice. Science286, 13771381.
  • 11
    Lau LL, Jamieson BD, Somasundaram T & Ahmed R (1994) Cytotoxic T-cell memory without antigen. Nature369, 648652.
  • 12
    Swain SL, Hu H & Huston G (1999) Class II-independent generation of CD4 memory T cells from effectors. Science286, 13811383.
  • 13
    Prlic M, Lefrancois L & Jameson SC (2002) Multiple choices: regulation of memory CD8 T cell generation and homeostasis by interleukin (IL)-7 and IL-15. J Exp Med195, F49F52.
  • 14
    Kondrack RM, Harbertson J, Tan JT, Mcbreen ME, Surh CD & Bradley LM (2003) Interleukin 7 regulates the survival and generation of memory CD4 cells. J Exp Med198, 17971806.
  • 15
    Lenz DC, Kurz SK, Lemmens E, Schoenberger SP, Sprent J, Oldstone MB & Homann D (2004) IL-7 regulates basal homeostatic proliferation of antiviral CD4+ T cell memory. Proc Natl Acad Sci USA101, 93579362.
  • 16
    Purton JF, Tan JT, Rubinstein MP, Kim DM, Sprent J & Surh CD (2007) Antiviral CD4+ memory T cells are IL-15 dependent. J Exp Med204, 951961.
  • 17
    Seddon B, Tomlinson P & Zamoyska R (2003) Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells. Nat Immunol4, 680686.
  • 18
    Nakajima H, Shores EW, Noguchi M & Leonard WJ (1997) The common cytokine receptor gamma chain plays an essential role in regulating lymphoid homeostasis. J Exp Med185, 189195.
  • 19
    Tan JT, Dudl E, Leroy E, Murray R, Sprent J, Weinberg KI & Surh CD (2001) IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc Natl Acad Sci USA98, 87328737.
  • 20
    Schluns KS, Kieper WC, Jameson SC & Lefrancois L (2000) Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat Immunol1, 426432.
  • 21
    Vivien L, Benoist C & Mathis D (2001) T lymphocytes need IL-7 but not IL-4 or IL-6 to survive in vivo. Int Immunol13, 763768.
  • 22
    Lodolce JP, Boone DL, Chai S, Swain RE, Dassopoulos T, Trettin S & Ma A (1998) IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity9, 669676.
  • 23
    Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M, Matsuki N, Charrier K, Sedger L, Willis CR et al. (2000) Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med191, 771780.
  • 24
    Jacobs SR, Michalek RD & Rathmell JC (2010) IL-7 is essential for homeostatic control of T cell metabolism in vivo. J Immunol184, 34613469.
  • 25
    Darnell JE Jr, Kerr IM & Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science264, 14151421.
  • 26
    Levy DE & Darnell JE Jr (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol3, 651662.
  • 27
    Nosaka T, Van Deursen JM, Tripp RA, Thierfelder WE, Witthuhn BA, Mcmickle AP, Doherty PC, Grosveld GC & Ihle JN (1995) Defective lymphoid development in mice lacking Jak3. Science270, 800802.
  • 28
    Thomis DC, Gurniak CB, Tivol E, Sharpe AH & Berg LJ (1995) Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science270, 794797.
  • 29
    Yao Z, Cui Y, Watford WT, Bream JH, Yamaoka K, Hissong BD, Li D, Durum SK, Jiang Q, Bhandoola A et al. (2006) Stat5a/b are essential for normal lymphoid development and differentiation. Proc Natl Acad Sci USA103, 10001005.
  • 30
    Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A et al. (1996) Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature379, 645648.
  • 31
    Flex E, Petrangeli V, Stella L, Chiaretti S, Hornakova T, Knoops L, Ariola C, Fodale V, Clappier E, Paoloni F et al. (2008) Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J Exp Med205, 751758.
  • 32
    Vainchenker W, Dusa A & Constantinescu SN (2008) JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol19, 385393.
  • 33
    Bessette K, Lang ML, Fava RA, Grundy M, Heinen J, Horne L, Spolski R, Al-Shami A, Morse HC III, Leonard WJ et al. (2008) A Stat5b transgene is capable of inducing CD8+ lymphoblastic lymphoma in the absence of normal TCR/MHC signaling. Blood111, 344350.
  • 34
    Kelly JA, Spolski R, Kovanen PE, Suzuki T, Bollenbacher J, Pise-Masison CA, Radonovich MF, Lee S, Jenkins NA, Copeland NG et al. (2003) Stat5 synergizes with T cell receptor/antigen stimulation in the development of lymphoblastic lymphoma. J Exp Med198, 7989.
  • 35
    Tonks NK (2006) Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol7, 833846.
  • 36
    Trowbridge IS & Thomas ML (1994) CD45: an emerging role as a protein tyrosine phosphatase required for lymphocyte activation and development. Annu Rev Immunol12, 85116.
  • 37
    Majeti R, Xu Z, Parslow TG, Olson JL, Daikh DI, Killeen N & Weiss A (2000) An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity. Cell103, 10591070.
  • 38
    Kishihara K, Penninger J, Wallace VA, Kundig TM, Kawai K, Wakeham A, Timms E, Pfeffer K, Ohashi PS, Thomas ML et al. (1993) Normal B lymphocyte development but impaired T cell maturation in CD45-exon6 protein tyrosine phosphatase-deficient mice. Cell74, 143156.
  • 39
    Byth KF, Conroy LA, Howlett S, Smith AJ, May J, Alexander DR & Holmes N (1996) CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation. J Exp Med183, 17071718.
  • 40
    Koretzky GA, Picus J, Thomas ML & Weiss A (1990) Tyrosine phosphatase CD45 is essential for coupling T-cell antigen receptor to the phosphatidyl inositol pathway. Nature346, 6668.
  • 41
    Williams JC, Wierenga RK & Saraste M (1998) Insights into Src kinase functions: structural comparisons. Trends Biochem Sci23, 179184.
  • 42
    Saunders AE & Johnson P (2010) Modulation of immune cell signalling by the leukocyte common tyrosine phosphatase, CD45. Cell Signal22, 339348.
  • 43
    Hermiston ML, Xu Z & Weiss A (2003) CD45: a critical regulator of signaling thresholds in immune cells. Annu Rev Immunol21, 107137.
  • 44
    Irie-Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, Welstead G, Griffiths E, Krawczyk C, Richardson CD, Aitken K et al. (2001) CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature409, 349354.
  • 45
    Wu L, Bijian K & Shen SH (2009) CD45 recruits adapter protein DOK-1 and negatively regulates JAK-STAT signaling in hematopoietic cells. Mol Immunol46, 21672177.
  • 46
    Penninger JM, Irie-Sasaki J, Sasaki T & Oliveira-Dos-Santos AJ (2001) CD45: new jobs for an old acquaintance. Nat Immunol2, 389396.
  • 47
    Ratei R, Sperling C, Karawajew L, Schott G, Schrappe M, Harbott J, Riehm H & Ludwig WD (1998) Immunophenotype and clinical characteristics of CD45-negative and CD45-positive childhood acute lymphoblastic leukemia. Ann Hematol77, 107114.
  • 48
    Lorenz U (2009) SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol Rev228, 342359.
  • 49
    Hof P, Pluskey S, Dhe-Paganon S, Eck MJ & Shoelson SE (1998) Crystal structure of the tyrosine phosphatase SHP-2. Cell92, 441450.
  • 50
    Pei D, Wang J & Walsh CT (1996) Differential functions of the two Src homology 2 domains in protein tyrosine phosphatase SH-PTP1. Proc Natl Acad Sci USA93, 11411145.
  • 51
    Dechert U, Adam M, Harder KW, Clark-Lewis I & Jirik F (1994) Characterization of protein tyrosine phosphatase SH-PTP2. Study of phosphopeptide substrates and possible regulatory role of SH2 domains. J Biol Chem269, 56025611.
  • 52
    Pei D, Lorenz U, Klingmuller U, Neel BG & Walsh CT (1994) Intramolecular regulation of protein tyrosine phosphatase SH-PTP1: a new function for Src homology 2 domains. Biochemistry33, 1548315493.
  • 53
    Townley R, Shen SH, Banville D & Ramachandran C (1993) Inhibition of the activity of protein tyrosine phosphate 1C by its SH2 domains. Biochemistry32, 1341413418.
  • 54
    Shultz LD, Schweitzer PA, Rajan TV, Yi T, Ihle JN, Matthews RJ, Thomas ML & Beier DR (1993) Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell73, 14451454.
  • 55
    Tsui HW, Siminovitch KA, De Souza L & Tsui FW (1993) Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nat Genet4, 124129.
  • 56
    Kozlowski M, Mlinaric-Rascan I, Feng GS, Shen R, Pawson T & Siminovitch KA (1993) Expression and catalytic activity of the tyrosine phosphatase PTP1C is severely impaired in motheaten and viable motheaten mice. J Exp Med178, 21572163.
  • 57
    Johnson KG, Leroy FG, Borysiewicz LK & Matthews RJ (1999) TCR signaling thresholds regulating T cell development and activation are dependent upon SHP-1. J Immunol162, 38023813.
  • 58
    Chiang GG & Sefton BM (2001) Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase. J Biol Chem276, 2317323178.
  • 59
    Lorenz U, Ravichandran KS, Burakoff SJ & Neel BG (1996) Lack of SHPTP1 results in src-family kinase hyperactivation and thymocyte hyperresponsiveness. Proc Natl Acad Sci USA93, 96249629.
  • 60
    Plas DR, Johnson R, Pingel JT, Matthews RJ, Dalton M, Roy G, Chan AC & Thomas ML (1996) Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling. Science272, 11731176.
  • 61
    Brockdorff J, Williams S, Couture C & Mustelin T (1999) Dephosphorylation of ZAP-70 and inhibition of T cell activation by activated SHP1. Eur J Immunol29, 25392550.
  • 62
    Cuevas B, Lu Y, Watt S, Kumar R, Zhang J, Siminovitch KA & Mills GB (1999) SHP-1 regulates Lck-induced phosphatidylinositol 3-kinase phosphorylation and activity. J Biol Chem274, 2758327589.
  • 63
    Stebbins CC, Watzl C, Billadeau DD, Leibson PJ, Burshtyn DN & Long EO (2003) Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity. Mol Cell Biol23, 62916299.
  • 64
    Lorenz U, Ravichandran KS, Pei D, Walsh CT, Burakoff SJ & Neel BG (1994) Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine T cells. Mol Cell Biol14, 18241834.
  • 65
    Stefanova I, Hemmer B, Vergelli M, Martin R, Biddison WE & Germain RN (2003) TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat Immunol4, 248254.
  • 66
    Fowler CC, Pao LI, Blattman JN & Greenberg PD (2010) SHP-1 in T cells limits the production of CD8 effector cells without impacting the formation of long-lived central memory cells. J Immunol185, 32563267.
  • 67
    Saxton TM, Henkemeyer M, Gasca S, Shen R, Rossi DJ, Shalaby F, Feng GS & Pawson T (1997) Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. EMBO J16, 23522364.
  • 68
    Qu CK, Nguyen S, Chen J & Feng GS (2001) Requirement of Shp-2 tyrosine phosphatase in lymphoid and hematopoietic cell development. Blood97, 911914.
  • 69
    Chan RJ, Johnson SA, Li Y, Yoder MC & Feng GS (2003) A definitive role of Shp-2 tyrosine phosphatase in mediating embryonic stem cell differentiation and hematopoiesis. Blood102, 20742080.
  • 70
    Xu D & Qu CK (2008) Protein tyrosine phosphatases in the JAK/STAT pathway. Front Biosci13, 49254932.
  • 71
    Stanford SM, Mustelin TM & Bottini N (2010) Lymphoid tyrosine phosphatase and autoimmunity: human genetics rediscovers tyrosine phosphatases. Semin Immunopathol32, 127136.
  • 72
    Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM et al. (2004) A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet75, 330337.
  • 73
    Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, Macmurray J, Meloni GF, Lucarelli P, Pellecchia M et al. (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet36, 337338.
  • 74
    Zhang J, Zahir N, Jiang Q, Miliotis H, Heyraud S, Meng X, Dong B, Xie G, Qiu F, Hao Z et al. (2011) The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness. Nat Genet43, 902907.
  • 75
    Menard L, Saadoun D, Isnardi I, Ng YS, Meyers G, Massad C, Price C, Abraham C, Motaghedi R, Buckner JH et al. (2011) The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J Clin Invest121, 36353644.
  • 76
    Zikherman J, Hermiston M, Steiner D, Hasegawa K, Chan A & Weiss A (2009) PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background. J Immunol182, 40934106.
  • 77
    Cloutier JF & Veillette A (1996) Association of inhibitory tyrosine protein kinase p50csk with protein tyrosine phosphatase PEP in T cells and other hemopoietic cells. EMBO J15, 49094918.
  • 78
    Chow LM, Fournel M, Davidson D & Veillette A (1993) Negative regulation of T-cell receptor signalling by tyrosine protein kinase p50csk . Nature365, 156160.
  • 79
    Cloutier JF & Veillette A (1999) Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J Exp Med189, 111121.
  • 80
    Gjorloff-Wingren A, Saxena M, Williams S, Hammi D & Mustelin T (1999) Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP. Eur J Immunol29, 38453854.
  • 81
    Hasegawa K, Martin F, Huang G, Tumas D, Diehl L & Chan AC (2004) PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science303, 685689.
  • 82
    Davidson D, Shi X, Zhong MC, Rhee I & Veillette A (2010) The phosphatase PTP-PEST promotes secondary T cell responses by dephosphorylating the protein tyrosine kinase Pyk2. Immunity33, 167180.
  • 83
    Simoncic PD, McGlade CJ & Tremblay ML (2006) PTP1B and TC-PTP: novel roles in immune-cell signaling. Can J Physiol Pharmacol84, 667675.
  • 84
    Ten Hoeve J, De Jesus Ibarra-Sanchez M, Fu Y, Zhu W, Tremblay M, David M & Shuai K (2002) Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol Cell Biol22, 56625668.
  • 85
    Yamamoto T, Sekine Y, Kashima K, Kubota A, Sato N, Aoki N & Matsuda T (2002) The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation. Biochem Biophys Res Commun297, 811817.
  • 86
    You-Ten KE, Muise ES, Itie A, Michaliszyn E, Wagner J, Jothy S, Lapp WS & Tremblay ML (1997) Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice. J Exp Med186, 683693.
  • 87
    Bourdeau A, Dube N, Heinonen KM, Theberge JF, Doody KM & Tremblay ML (2007) TC-PTP-deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-{gamma}. Blood109, 42204228.
  • 88
    Dupuis M, De Jesus Ibarra-Sanchez M, Tremblay ML & Duplay P (2003) Gr-1+ myeloid cells lacking T cell protein tyrosine phosphatase inhibit lymphocyte proliferation by an IFN-gamma- and nitric oxide-dependent mechanism. J Immunol171, 726732.
  • 89
    Wiede F, Shields BJ, Chew SH, Kyparissoudis K, Van Vliet C, Galic S, Tremblay ML, Russell SM, Godfrey DI & Tiganis T (2011) T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. J Clin Invest121, 47584774.
  • 90
    Simoncic PD, Lee-Loy A, Barber DL, Tremblay ML & McGlade CJ (2002) The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3. Curr Biol12, 446453.
  • 91
    Kleppe M, Lahortiga I, El Chaar T, De Keersmaecker K, Mentens N, Graux C, Van Roosbroeck K, Ferrando AA, Langerak AW, Meijerink JP et al. (2010) Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia. Nat Genet42, 530535.
  • 92
    Sergienko E, Xu J, Liu WH, Dahl R, Critton DA, Su Y, Brown BT, Chan X, Yang L, Bobkova EV et al. (2012) Inhibition of hematopoietic protein tyrosine phosphatase augments and prolongs ERK1/2 and p38 activation. ACS Chem Biol7, 367377.
  • 93
    Saxena M, Williams S, Brockdorff J, Gilman J & Mustelin T (1999) Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP). J Biol Chem274, 1169311700.
  • 94
    Gronda M, Arab S, Iafrate B, Suzuki H & Zanke BW (2001) Hematopoietic protein tyrosine phosphatase suppresses extracellular stimulus-regulated kinase activation. Mol Cell Biol21, 68516858.
  • 95
    Francis DM, Rozycki B, Koveal D, Hummer G, Page R & Peti W (2011) Structural basis of p38alpha regulation by hematopoietic tyrosine phosphatase. Nat Chem Biol7, 916924.
  • 96
    Pettiford SM & Herbst R (2000) The MAP-kinase ERK2 is a specific substrate of the protein tyrosine phosphatase HePTP. Oncogene19, 858869.
  • 97
    Sozio MS, Mathis MA, Young JA, Walchli S, Pitcher LA, Wrage PC, Bartok B, Campbell A, Watts JD, Aebersold R et al. (2004) PTPH1 is a predominant protein-tyrosine phosphatase capable of interacting with and dephosphorylating the T cell receptor zeta subunit. J Biol Chem279, 77607769.
  • 98
    Bauler TJ, Hughes ED, Arimura Y, Mustelin T, Saunders TL & King PD (2007) Normal TCR signal transduction in mice that lack catalytically active PTPN3 protein tyrosine phosphatase. J Immunol178, 36803687.
  • 99
    Zhang Y, Reynolds JM, Chang SH, Martin-Orozco N, Chung Y, Nurieva RI & Dong C (2009) MKP-1 is necessary for T cell activation and function. J Biol Chem284, 3081530824.
  • 100
    Zhang Y, Blattman JN, Kennedy NJ, Duong J, Nguyen T, Wang Y, Davis RJ, Greenberg PD, Flavell RA & Dong C (2004) Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5. Nature430, 793797.
  • 101
    Huang G, Wang Y, Shi LZ, Kanneganti TD & Chi H (2011) Signaling by the phosphatase MKP-1 in dendritic cells imprints distinct effector and regulatory T cell fates. Immunity35, 4558.
  • 102
    Blanchetot C, Chagnon M, Dube N, Halle M & Tremblay ML (2005) Substrate-trapping techniques in the identification of cellular PTP targets. Methods35, 4453.
  • 103
    Garton AJ, Burnham MR, Bouton AH & Tonks NK (1997) Association of PTP-PEST with the SH3 domain of p130cas; a novel mechanism of protein tyrosine phosphatase substrate recognition. Oncogene15, 877885.
  • 104
    Bourdeau A, Dube N & Tremblay ML (2005) Cytoplasmic protein tyrosine phosphatases, regulation and function: the roles of PTP1B and TC-PTP. Curr Opin Cell Biol17, 203209.
  • 105
    Edmonds SD & Ostergaard HL (2002) Dynamic association of CD45 with detergent-insoluble microdomains in T lymphocytes. J Immunol169, 50365042.
  • 106
    Fawcett VC & Lorenz U (2005) Localization of Src homology 2 domain-containing phosphatase 1 (SHP-1) to lipid rafts in T lymphocytes: functional implications and a role for the SHP-1 carboxyl terminus. J Immunol174, 28492859.
  • 107
    Seavitt JR, White LS, Murphy KM, Loh DY, Perlmutter RM & Thomas ML (1999) Expression of the p56(Lck) Y505F mutation in CD45-deficient mice rescues thymocyte development. Mol Cell Biol19, 42004208.
  • 108
    Mcneill L, Cassady RL, Sarkardei S, Cooper JC, Morgan G & Alexander DR (2004) CD45 isoforms in T cell signalling and development. Immunol Lett92, 125134.
  • 109
    Mcneill L, Salmond RJ, Cooper JC, Carret CK, Cassady-Cain RL, Roche-Molina M, Tandon P, Holmes N & Alexander DR (2007) The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses. Immunity27, 425437.