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Keywords:

  • chemokine;
  • follicles;
  • germinal centre;
  • secondary lymphoid organ;
  • T-cell help

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. T-cell access to B-cell follicles and GC
  5. T-cell distribution within GC
  6. Functional activity of follicular associated CD4 T cells
  7. Regulation of TH cells within B-cell follicles and GC
  8. Concluding remarks
  9. Acknowledgments
  10. References

The immune system utilizes sophisticated cellular surveillance mechanisms to maintain the integrity of the multicellular host. Adaptive immunosurveillance in particular constitutes a powerful branch of the immune system that houses the capacity to mount exquisitely specific responses against a diverse array of foreign antigens. Central to the development of adaptive immunity is the activation of T and B cells. Upon antigen engagement, T and B cells have been observed to undergo striking changes in their migratory status and distribution within secondary lymphoid organs, a phenomenon that is to a large extent controlled through their altered responsiveness to homeostatic T- and B-zone chemokines. Changes in their chemokine receptor expression and/or sensitivity to their respective ligands assist in bringing rare antigen-specific T and B lymphocytes, dendritic cells and CD4+CD3 accessory cells together. Cognate interaction between these cells at the T–B junction can support the generation of extrafollicular foci of antibody producing plasma cells and the formation of germinal centers. Such T-dependent antibody responses are highly dependent on the functional properties and activity of a specialized subset of CXCR5+ICOS+ CD4 T cells referred to as T follicular helper cells (TFH). This review presents an overview of some of the defining characteristics of this subset of T-helper cells and the chemokine receptors and their ligands that help dictate the migratory activity of TFH cells within secondary lymphoid organs.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. T-cell access to B-cell follicles and GC
  5. T-cell distribution within GC
  6. Functional activity of follicular associated CD4 T cells
  7. Regulation of TH cells within B-cell follicles and GC
  8. Concluding remarks
  9. Acknowledgments
  10. References

Chemokines and T-dependent antibody responses

Given the low frequency of circulating lymphocytes for any given antigen, a principal function of secondary lymphoid organs is to bring antigen-presenting cells and lymphocytes into close physical contact (1). This ensures the efficient generation of adaptive immune responses to invading pathogens. Within secondary lymphoid organs, one of the most significant outcomes of these interactions is the establishment of germinal centres (GCs), from which high-affinity antibody-secreting plasma cells and long-lived memory B cells are generated (2); a process that is highly dependent on CD4 T-cell help (3). Homeostatic or lymphoid chemokines play an instrumental role in coordinating these T-dependent antibody responses, by guiding leukocyte migration and regulating their spatial distribution within secondary lymphoid organs (1). Cell migration in response to chemokines is mediated via G-protein-coupled receptors (4). Included within the lymphoid subset of chemokines are CCL19 [Epstein-Barr virus-induced receptor ligand chemokine (ELC)] and CCL21 [secondary lymphoid tissue chemokine (SLC)] and their shared receptor CCR7; CXCL13 [B-lymphocyte chemokine (BLC)] and its receptor CXCR5; and CXCL12 [stromal cell-derived factor-1 (SDF-1)] and its receptor CXCR4 (1).

Expression of CXCR5 on mature, recirculating B cells facilitates their movement from the blood into B-cell follicles, which are enriched for the chemokine CXCL13 (5). Upon antigen capture, B cells upregulate the expression of the chemokine receptor CCR7, while keeping CXCR5 expression levels unchanged, and acquire an enhanced responsiveness to the T-zone chemokines CCL21 and CCL19 (6). The subsequent change in chemokine responsiveness within antigen-engaged B cells permits their relocalization to the boundary of the T zone; an opportunistic location for eliciting T-cell help (7).

Indeed, an important function of CD4 T cells is to serve as B-cell helpers (8). Naïve T-cell migration into secondary lymphoid organs occurs in a CCR7-dependent manner (9). However, upon antigen engagement, many CD4 T cells upregulate CXCR5 and become responsive to the follicular associated chemokine CXCL13 (10). While the level of CXCR5 expression on activated CD4 T cells does not equal that of B cells, they have been shown to display a greater sensitive to lower doses of CXCL13 than B cells (10). The finding that naïve CXCR5 transgenic CD4 T cell could also respond chemotactically to lower doses of CXCL13 than B cells, indicates that this difference in responsiveness to the follicular associated chemokine is because of an intrinsic difference between T and B cells and is not related to the activation status of the cells (11). Conversely, these activated T cells become less responsive to the T-zone chemokines CCL21 and CCL19 through the down-modulation of CCR7 expression levels (10). Together, these changes in chemokine responsiveness account for the follicular localization of T cells and the ability of these cells to provide help to B cells and support GC development (11–13) (Figure 1A). Indeed, T cells isolated from lymphoid tissues based on CXCR5 expression were found to be capable of supporting B-cell proliferation and antibody production in vitro (14–17). Given the anatomical location of CXCR5+ CD4 T cells within secondary lymphoid organs, their distinct cell surface phenotypes and cytokine and gene-expression profiles from that of T-helper (TH) 1 and TH2 cells (18, 19), this TH-cell subset was so coined follicular B helper T cells (TFH).

image

Figure 1. CXCR5-mediated distribution of CD4 T-helper cells during a T-dependent antibody response. (A) Immunohistochemistry on a cryostat section of a lymph node isolated from an immunized C57BL/6 mouse. The section was stained for immunoglobulin (Ig)D (brown) to identify the lymph node follicles and anti-CD3ε (blue) to locate all T cells. As GC cells down-modulate the expression of IgD, the IgD negative zone within the B-cell follicle delineates the location of the GC reaction. Objective magnification, 5×. (B–D) Schematic diagram comparing the distribution of wild type (X5+/+) and CXCR5−/− (X5−/−) T cells within a lymph node during the various phases of a T-dependent antibody response. (B) Upon antigen engagement many CD4 T cells begin to upregulate the expression of CXCR5 and conversely down-modulation their CCR7 expression levels (Box 1). Recent data would suggest that T-cell localization to the outer T zone and early cognate T–B cell interactions, resulting in the generation of extrafollicular foci of antibody-producing plasma cells, can occur in a CXCR5-independent manner (Box 1). Other factors such as the down-modulation of CCR7 may contribute to the redirected movement of peptide/MHC-activated CD4 T cells. (C) T-cell access to B-cell follicles, certainly prior to establishment of GCs is dependent on T-cell expression of CXCR5 (Box 2). T cells, deficient of CXCR5, are incapable of migrating beyond the T–B boundary. (D) CXCR5-deficient T cells can support the development of GCs within follicles; however, these are typically smaller that those GCs supported by wild-type T cells. Interestingly, at least some CD4 T cells can gain direct access to GCs from the T zone in a CXCR5-independent manner (Box 3). This observation highlights the likelihood that other chemoattractants and/or B-cell supported mechanisms are involved in promoting T-cell migration into the GC microenvironment.

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T-cell access to B-cell follicles and GC

  1. Top of page
  2. Abstract
  3. Introduction
  4. T-cell access to B-cell follicles and GC
  5. T-cell distribution within GC
  6. Functional activity of follicular associated CD4 T cells
  7. Regulation of TH cells within B-cell follicles and GC
  8. Concluding remarks
  9. Acknowledgments
  10. References

Follicular associated CD4+ T cells were first identified in the GCs of human tonsils almost 20 years ago (20). Since then, it has become clear that this T-cell subset is extremely heterogenous in both phenotype and function (8, 21). Until recently, the best defining marker(s) of follicular associated CD4 T cells has been CXCR5 and CD57 in human tissues and CXCR5 in mouse tissues. However, further characterization of GC T cells, bearing B-cell helper qualities, has now shown that the selective loss of interleukin (IL)-7Rα to be one the best defining features of terminally differentiated human FTH cell (22). The chemokine receptor, CXCR5 is not detectable on naïve CD4 T cells or fully differentiated TH1 and TH2 cells but can be found on a small subset of peripheral-blood and tonsillar memory CD4 T cells as well as a subset of memory CD8 T cells (23). TH cells begin upregulating CXCR5 within a few days of antigen recognition, achieving maximal levels within 5 days of stimulation (10). At what point CD4 T cells commit to becoming a TFH cell and what signals dictate their divergence from the TH1/TH2 lineage commitment pathways still remains unclear.

The expression of CXCR5 has been confirmed to be necessary for T-cell entry into primary B-cell follicles (11,13) (Figure 1C). However, whether the increased expression levels of CXCR5 on T cells is required to promote early collaborations with B cells at the outer T zone, leading to the generation of extrafollicular foci of plasmablasts, is still questionable. While CXCR5 deficiency in T cells has previously been shown to limit immunoglobulin (Ig)G serum antibody responses (12, 13, 24), it has not been clear as to whether this reflects a role for CXCR5 in early T–B interactions vs guiding the cells into follicles or whether the deficiency may have altered events that may subsequently impact GC formation and/or function. More recent data would support the latter as T cells deficient for CXCR5 were found to be capable of supporting normal antibody responses in vivo; however, the developing GC were typically two to three times smaller than those supported by wild-type T cells (11). These data suggesting that T-cell movement to the T–B boundary can occur in a CXCR5-independent manner (Figure 1B). It is likely that other factors, such as the down-modulation of CCR7 may help in coordinating the redirected movement of TH cells to the outer T zone following antigen engagement. Indeed reduced expression of CCR7 on T cells has been associated with a preference to move to the outer T zone (25).

Coinciding with the upregulation of CXCR5 is the expression of the costimulatory molecule OX-40 (26). Indeed, stimulation via the costimulatory molecule CD28 together with OX-40 can help augment the induction of CXCR5 mRNA expression (27). The OX-40 ligand is expressed on CD40-activated DC (28, 29) as well as CD4+CD3 accessory cells, which have also been observed to reside within the vicinity of the T–B boundary (30). Several studies using in vivo models have shown that signals delivered via OX-40/OX-40L interactions have the capacity to influence T-cell entry into follicles. In mice, in which DC overexpressing the OX-40L, increased numbers of T cells were found to accumulate within the follicles (28), whereas T cells deficient of OX-40 failed to migrate into follicles and the subsequent expansion of GC B cells was reduced in immunized mice (26).

While it has been clearly established that a shift in chemokine responsiveness in favor of CXCL13 is required for T-cell movement into follicles, other factors may also contribute to the redistribution of T-cell help during a T-dependent antibody response (11). Highlighting this point was the recent observation that CXCR5-deficient T cells could gain access to GCs forming within B-cell follicles (Figure 1D). It should be noted, however, that the number of CXCR5-deficient GC-associated T cells was significantly smaller than that observed in GCs supported by wild-type T cells (11, 12). The mechanisms supporting such movement from the T zone are unclear but may reflect the existence of additional GC-specific attractants. Alternatively, because activated T and B cells can form stable conjugates, in which only the B cell remains motile, it is possible that the T cells are dragged into the GC with cognate B-cell partners during the formation of the GC (7).

T-cell distribution within GC

  1. Top of page
  2. Abstract
  3. Introduction
  4. T-cell access to B-cell follicles and GC
  5. T-cell distribution within GC
  6. Functional activity of follicular associated CD4 T cells
  7. Regulation of TH cells within B-cell follicles and GC
  8. Concluding remarks
  9. Acknowledgments
  10. References

GC formation is dependent on CD4 T-cell help (3). Indeed, GCs that form in response to T-independent antigens collapse early after induction suggesting that signals from T cells are essential for maintaining the response (31, 32). Once within the GC microenvironment, T cells through a CXCR5-mediated process accumulate within the T-zone distal pole of the GC, known as the light zone (11). This compartment of the GC is enriched for CXCL13 (33) and is the site in which GC B cells bearing high-affinity B-cell receptors are thought to be selected based on their ability to compete for antigen and elicit T-cell help (34). Those selected give rise to plasma cells or become part of the memory B-cell pool. Within the light zone, CXCL13 accumulates on the processes of follicular DC (35). However, gene expression profiles have shown that GC-associated TFH also express this chemokine (19). While the levels to which TH cells express and produce CXCL13 is still unclear, these data do open up the possibility that GC-T cells may have the capacity to create their own microenvironment within GCs, into which they can recruit B cells. Few T cells localize within the SDF-1-enriched dark zone of the GC (11), a site in which rapidly proliferating B cells undergoing somatic hypermutation of their antibody-variable region genes (2). Human GC T cells have been reported to express CXCR4 but were found to be poorly responsive to the CXCR4 ligand, SDF-1 in vitro (36). Indeed, CXCR5-deficient GC-associated T cells do not display an increased propensity to accumulate within the GC dark zone (11), suggest a very limiting role for CXCR4 in coordinating T-cell positioning within the GC microenvironment.

Functional activity of follicular associated CD4 T cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. T-cell access to B-cell follicles and GC
  5. T-cell distribution within GC
  6. Functional activity of follicular associated CD4 T cells
  7. Regulation of TH cells within B-cell follicles and GC
  8. Concluding remarks
  9. Acknowledgments
  10. References

The pathway through which TFH cells acquire their B-helper cell properties is unclear (37). CXCR5+ T cells are nonpolarized with respect to TH1/TH2 cytokine production and the transcription factors, which dictate the differential status of this TH-cell subset, have yet to be defined (38). However, the finding that the transcription factor BCL6 is preferentially expressed within the CXCR5+ TFH cells did raise the possibility that this transcriptional repressor may play a role in regulating the differentiation and function of TFH cells (18). Best known for its role in regulating B-cell differentiation, BCL6 directs GC lineage commitment in part through the repression of the GATA-binding protein 3 (GATA3) (39, 40). In T cells, GATA3 drives TH2 cytokine production, so it is conceivable that BCL6 repression of GATA3 may be a deciding factor in TFHvs TH2 lineage commitment (41). What signals promote BCL6 expression within T cells is not clear but it is possible that interactions with DC, CD4+CD3 accessory cells and/or B cells at the outer T zone or within follicles may drive its expression and subsequent function. Indeed, B cells have been reported to directly dictate the nature of the T-cell help that they require. In an in vitro system, B cells were shown to be capable of soliciting their own help from T cells through altering their expression of the costimulatory molecules CD70 and ICOS and promoting their capacity to produce IL-10 (42), which is known to support immunoglobulin production by human B cells (43).

T-cell help to B cells can be provided through a number of factors. The best described of these is CD40L, which binds CD40 on B cells during both the early T–B interactions at the outer T zone and during centrocyte selection within GCs (44). The CD40L/CD40 collaboration is crucial for the induction of B-cell proliferation, class switching and memory B-cell differentiation. Other molecules that have been shown to be necessary for T-cell help to B cells include the costimulatory molecules CD28 and ICOS, cytokines such as IL-21 and IL-4 and the signaling lymphocytic activation molecule (SLAM)-associated protein (SAP).

It has been well documented that optimal T-cell activation requires signals to be delivered via both the TCR and CD28. In mice rendered deficient of CD28 signaling through the constitutive expression of a soluble CD28 competitor CTLA-4-Ig, T-cell driven GC responses fail to develop because of the lack of CXCR5+ T-cell help (26), a phenomenon that is likely associated with the compromised expression of OX-40 in the T cells of these mice, which has been linked with T-cell migration into B-cell follicles. More recently, the costimulatory molecule ICOS, a member of the CD28 family of costimulatory molecules, was also found to play a role in regulating CXCR5 expression and subsequently supporting the development and maintenance of CXCR5+ TFH cells in vivo (45, 46). Expression of ICOS is restricted to activated T cells, including TH2 cells (47); indeed, the expression of ICOS on human CXCR5+ T cells was proposed as being a defining marker of a terminally differentiated follicular associated TH cell (48). The ligand for ICOS, ICOSL (also known as B7RP-1, B7h, B7-H2, GL50 and LICOS), is constitutively expressed on B cells as well as DC and macrophages (49). Mice deficient of ICOS or ICOSL develop fewer and smaller GC and display a defect in IgG1 antibody production following immunization with a T-dependent antigen (50–53). Activated CD4 T cells in these mice can migrate into B-cell follicles but have a reduced capacity to produce IL-4 and IL-10, which have both been intimately linked with the regulation of B-cell responses in mice and humans. In humans, ICOS deficiency results in the development of common variable immunodeficiency, in which they fail to generate memory B cells and immunoglobulin class switching does not occur (43, 54). Certainly, ICOS plays a crucial role in supporting T-cell-dependent antibody responses; however, it is still unclear as to whether the effect of ICOS deficiency on TFH-cell development is direct or secondary to the failure in GC formation.

In addition to costimulatory molecules, TH-cell production of cytokines also has a significant influence on T-dependent B-cell responses. Human TFH cells have been shown to produce IL-10 and mouse CXCR5+ T cells have been found to express high IL-4 transcript levels, characteristic of TH2 cells (11). A third cytokine associated with TFH-cell function is IL-21 (18, 55). IL-21 is a member of the common γ-chain cytokine family and to date activated CD4 T cells are the only cell type found to express it (56). Of the TH subsets, TFH cells preferentially express IL-21; however, TH1 cells have also been shown to express consistently high levels of the cytokine (18). The receptor for IL-21 can be found on T, B and natural killer (NK) cells (56, 57). Within the B-cell lineage, IL-21 has been shown to regulate B-cell expansion and differentiation into antibody producing plasma cells; a phenomenon that is in part regulated by IL-21-mediated control of the expression levels of the plasma-cell-associated transcription factor – Blimp-1, and the GC-cell-associated transcription factor – BCL6 (55, 58–61).

The requirement for SAP in TH-cell function was identified from the findings that both humans and mice bearing mutations affecting the gene encoding SAP, SH2D1A had a significantly reduced capacity to mount T-dependent antibody responses (62, 63). SAP is an intracellular protein, which is expressed in T, NK, NKT and B cells. It binds to members of the SLAM family of transmembrane receptors, including SLAM/CD150, CD84 and CD229; which are typically coexpressed with CXCR5 in TFH cells (18), CD244/2B4 and NTB-A/Ly-108 (62). While SAP is involved in a vast array of lymphocyte functions, the humoral defects associated with SAP deficiency; such as impaired B-cell proliferation and defective GC formation is largely T-cell dependent (64). Indeed, SAP-deficient CD4 T cells have been shown to be defective in TCR-mediated TH2 cytokine production in vitro and to have dysregulated ICOS and CD40L expression levels, which are both critical regulators of GC formation (65). The interaction of SAP with the self-ligating SLAM family of receptors can induce the recruitment of the Src family kinase Fyn and permit receptor tyrosine phosphorylation and subsequent signal transduction (62, 66). However, recently it was reported that the SAP-dependent acquisition of B-cell helper functions by CD4 T cells could be regulated independently of the SLAM–SAP–Fyn signaling pathway (64), which is thought to be involved in the regulation of TH1/TH2 differentiation (67). It will now be interesting to ascertain which of the SLAM family of receptors may contribute in determining whether a CD4 T-cell becomes differentially committed to becoming a TFH cell versus a TH1 or TH2 cell.

Regulation of TH cells within B-cell follicles and GC

  1. Top of page
  2. Abstract
  3. Introduction
  4. T-cell access to B-cell follicles and GC
  5. T-cell distribution within GC
  6. Functional activity of follicular associated CD4 T cells
  7. Regulation of TH cells within B-cell follicles and GC
  8. Concluding remarks
  9. Acknowledgments
  10. References

During a T-dependent antibody response B-cell proliferation, differentiation, affinity maturation and survival are to a large extent dictated through their cognate interactions with TH cells. While responsible for driving B-cell responses to T-cell antigens, TH-cell activity must also be tightly regulated if peripheral B-cell tolerance is to be maintained. Certainly, there are multiple checkpoints regulating cognate T–B interactions and the subsequent production of antibody-secreting cells and long-lived memory B cells (68). In the case of TFH cells, the regulation of ICOS expression and its function as well as the upregulation of negative costimulatory molecules such as CTLA-4 and program death receptor-1 (PD-1) may help regulate the extent to which T cells can deliver assistance to B cells (69). It is also highly possible that T-regulatory cells, some of which express CXCR5 and can localize within GCs (70), may further influence the availability of T-cell help within the B-cell areas of secondary lymphoid organs.

Given the role for ICOS in supporting TFH-cell development and maintenance and its role in providing critical costimulatory signals to GC B cells, the tight regulation of ICOS expression in these cells is necessary to limit the generation of self-reactive TH cells and restrict the inappropriate selection of self-reactive B cells within GC. Recently, a repressor of ICOS function was identified through the characterization of the sanroque mouse strain (71). This mouse presented with severe autoimmune disease resulting from a single recessive mutation within the Roquin gene, which encodes for an E3 ubiquitin ligase. The mutation was found to act within mature T cells causing the formation and accumulation of excessive numbers of CXCR5+ICOSHi T cells and GC within the B-cell area of lymphoid tissues. The cell-autonomous dysregulation of sanroque T cells could be corrected through the retroviral expression of wild-type Roquin. It has been proposed that the mechanism of action of Roquin may link ubiquitylation with the regulation of mRNA stability or translation. The immediate targets of this enzyme, however, have not been clearly defined, but could include ICOS, IL-21 and/or SAP (71).

In addition to the upregulation of costimulatory molecules, antigen exposed CXCR5+ GC-associated T cells also express high levels of negative costimulatory molecules such as PD-1 (11, 72, 73). Several studies have indicated that chronic exposure of CD4 and CD8 T cells to cognate antigen can induce high levels of PD-1 expression (74). It has been proposed that the high level of PD-1 on GC T cells is secondary to repeated interactions with activated, antigen-bearing B cells in the GC (11). The ligands for PD-1, PD-L1 and PD-L2 are widely expressed, including expression on T cells, B cells, macrophages and DC (75); however, it is still not clear as to what extent they are expressed within the GC microenvironment. Despite this, studies are ongoing to determine whether PD-1 does function as an inhibitory receptor on follicular TH cells within the GC, in that it may help prevent newly emerging autoreactive B cells from receiving T-cell help. Signaling via the inhibitory receptor CTLA-4 may also limit the availability of T-cell help within B-cell follicle and GC reactions. By what mechanisms CTLA-4 mediates this suppression has not been clearly defined; however, engagement of this inhibitory receptor has been shown to limit the activity of ICOS (76). It will be interesting to assess whether PD-1 on GC T cells can work in collaboration with CTLA-4 to increase the threshold of the major histocompatibility complex (MHC)-peptide recognition that is needed to overcome negative signaling and permit a helper response.

Concluding remarks

  1. Top of page
  2. Abstract
  3. Introduction
  4. T-cell access to B-cell follicles and GC
  5. T-cell distribution within GC
  6. Functional activity of follicular associated CD4 T cells
  7. Regulation of TH cells within B-cell follicles and GC
  8. Concluding remarks
  9. Acknowledgments
  10. References

Much is still to be learnt about the phenotype, function and ultimate fate of follicular associated T cells that house the capacity to support B-cell antibody responses to T-cell antigens. Gene array analysis and the use of gene-targeted mice have shown a great deal about the molecular candidates, which can help define TFH cells from that of TH1/TH2 cells both phenotypically and functionally. However, now with the recent findings that CXCR5HiCCR7LoICOS+ GC T cells express high levels of PD-1 in the mouse and are selectively negative for IL-7Rα in human tissues, this should greatly assist in our ability to isolate these TH cells for further characterization and track their development and differentiation in vivo. In addition to this, the finding that GC T cells do express high levels of PD-1 does establish solid grounds to further explore the role of inhibitory receptors within GC. Another important aspect of TFH cells, which has not been explored in great detail, is the subsequent fate of these cells upon retraction of the immune response. While CXCR5-mediated T-cell entry into B-cell follicles is critical for the development and persistence of a robust GC reaction, it is still not clear as to what benefit the follicular microenvironment offers to TH cells and their subsequent fate. Related to this, a recent study did demonstrate that reservoirs of antigen-specific CXCR5+ICOSlo TFH cells could persist within draining lymphoid sites with antigen specific memory B cells (77). To extend these findings it will now be interesting to determine whether persistent cognate interactions between T and B cells and/or CD4+CD3 accessory cells, within the follicular microenvironment, can promote the survival of a subset of helper T cells and in turn support the development of a memory CD4 T-cell pool.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. T-cell access to B-cell follicles and GC
  5. T-cell distribution within GC
  6. Functional activity of follicular associated CD4 T cells
  7. Regulation of TH cells within B-cell follicles and GC
  8. Concluding remarks
  9. Acknowledgments
  10. References

The author would like to thank Prof. J. G. Cyster for his helpful comments on the manuscript. Some of the work on which this review was based on was performed in Prof. J. G. Cyster’s laboratory in the Department of Microbiology and Immunology at the University of California, San Francisco, CA 94143-0414, USA. This work was supported by the NHMRC of Australia CJ Martin Fellowship.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. T-cell access to B-cell follicles and GC
  5. T-cell distribution within GC
  6. Functional activity of follicular associated CD4 T cells
  7. Regulation of TH cells within B-cell follicles and GC
  8. Concluding remarks
  9. Acknowledgments
  10. References
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