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Keywords:

  • Chemokines;
  • integrin;
  • selectin;
  • Treg

Common Concepts in Leukocyte Trafficking/Migration

  1. Top of page
  2. Common Concepts in Leukocyte Trafficking/Migration
  3. Treg Chemokine Receptors and Responses
  4. Integrins, Selectins and Treg Migration
  5. Treg Homeostatic Trafficking To and Within Lymphoid Organs
  6. Other Regulators of Leukocyte Migration and Their Potential Role in Treg Migration
  7. Treg Regulate Migration of Other Leukocytes
  8. Conclusions
  9. Acknowledgments
  10. References

Immune responses require the orchestrated migration of leukocytes throughout the body, trafficking among lymphoid organs and nonlymphoid organs or positioning inside lymphoid organs. Leukocyte migration depends largely on the recognition of a chemoattractant gradient and adhesive interaction with the substratum, for three distinct events: vascular attachment, transendothelial migration and tissue migration under chemotaxis. These events are mediated by leukocyte expression of surface adhesion and chemoattractant receptors (1,2). Cell adhesion molecules (CAMs) necessary for leukocyte migration include selectins, integrins and members of the large immunoglobulin gene superfamily. By interacting with their glycoprotein ligands, selectins create weak bonds between activated endothelial cells (E- and P-selectin) and leukocytes (L-selectin), enabling the leukocytes in the postcapillary venules to roll and tether along the inner endothelial surface (3). Then, chemokine-induced activation leads to a conformational change in the leukocyte integrins, which together with the relevant CAMs expressed on endothelium, result in firm adhesion and transmigration of leukocytes (4). The final positioning of the extravasated leukocytes in the extracellular matrix is probably regulated by chemoattractant gradients in conjunction with integrin-based adhesion interactions with common matrix proteins, like collagen.

Lymphocyte trafficking is regulated by an extensive network of chemoattractants, and our understanding of the chemoattractants is expanding rapidly. Chemoattractic molecules include chemokines, cytokines, inflammatory lipid mediators such as leukotrienes and prostaglandins, antimicrobial peptides such as defensins and chemerin, microbial products such as fMet-Leu-Phe and complement proteins such as C3a and C5a. Chemokines have been recognized as the most dedicated chemoattractants in regulating leukocyte trafficking and positioning in both homeostatic and inflammatory conditions. They are a group of chemotactic cytokines that signal through seven transmembrane-spanning receptors coupled to G-proteins. There are more than 40 chemokines identified to date, which are classified according to the configuration of cysteine residues near the N-terminus into CC−, CXC−, C− and CX3C chemokines. They can also be classified into ‘inflammatory/inducible’ and ‘homeostatic/lymphoid’ chemokines based on the site of production and the eliciting stimuli (5).

Treg Chemokine Receptors and Responses

  1. Top of page
  2. Common Concepts in Leukocyte Trafficking/Migration
  3. Treg Chemokine Receptors and Responses
  4. Integrins, Selectins and Treg Migration
  5. Treg Homeostatic Trafficking To and Within Lymphoid Organs
  6. Other Regulators of Leukocyte Migration and Their Potential Role in Treg Migration
  7. Treg Regulate Migration of Other Leukocytes
  8. Conclusions
  9. Acknowledgments
  10. References

A number of studies have examined Treg chemotaxis, migration and receptor expression (Table 1). While many different chemokine receptors have been reported to be important for Treg homing to and function in tissues, there is little agreement among the reports. Iellem et al. have shown that although some chemokines stimulate the migration of both resting human CD4+CD25+ and CD4+CD25− T cells, CD25+ cells specifically express the chemokine receptors CCR4 and CCR8 (6), and migrate in response to their ligands CCL17 and CCL1, respectively (7). Curiel et al. studied 104 individuals affected with ovarian carcinoma and found that human Treg preferentially move to and accumulate in tumors and ascites, mediated by tumor cells and microenviromental macrophages producing CCL22 (ligand of CCR4), but rarely enter draining lymph nodes (8). Murine studies have indicated that CCL4 preferentially attracts CD25+ Treg, and its receptor CCR5 is expressed on these cells (9). Wysocki et al. demonstrated that Treg lacking expression of CCR5 were far less effective in preventing lethality from graft-vs-host disease (GVHD) (10). Lee et al. showed in a murine cardiac transplant model that the recruitment of Foxp3-expressing Treg to the allograft is dependent on CCL17-CCR4 (11).

Table 1.  Chemokine/chemokine receptor usage by Treg
SpeciesTreg typeChemokine/receptor involvedModelReference
HumanCD4+CD25+CCL22/CCR4. CCL1/CCR8In vitro6,7
MouseCD4+CD25+CCL4In vitro10
MouseCD4+CD25+CCR5GVHD11
MouseCD4+CD25+CCL17/CCR4Cardiac transplantation8
HumanCD4+CD25+CCL22/CCR4Ovarian carcinoma9
MouseCD4+CD25+CCR6EAE15
MouseCD4+CD25+CD62L+CCR7NOD34
CD4+CD25+CD62L−CCR2, CCR4, CXCR3 

It is noteworthy that antigen presenting cells (APCs) and activated B and T cells are good sources of ligands of chemokines. Activated B cells produce CCL17 (CCR4 ligands) and CCL4 (CCR5 ligands) (8,12); mature dendritic cells secrete significant amounts of CCL17 (13); and monocytes or macrophages and activated T cells are major producers of CCL1 (CCR8 ligand) (14). Since Treg regulate immune responses directly through interacting with T effector cells or indirectly through modifying APCs, the preferential expression of CCR4, CCR5, CCR8 by Treg may guide them to their cellular targets and control their interaction with APCs and T cells. Gene array analysis of mouse CD4+CD25+ T cells and CD4+CD25− T cells showed mRNA encoding CCR6 was significantly more abundant on CD4+CD25+ Treg, and the authors concluded that CCR6 expression defines regulatory effector/memory-like cells within the CD4+CD25+ T cells (15).

In summary (Table 1), Treg have been described by different groups as bearing exclusively, or higher levels of CCR4, CCR8 or CCR6; responding or not responding to lymphoid chemokines CCL19, CCL21, CXCL12, homeostatic chemokines CCL22, CCL17 and inflammatory chemokines CCL2, CXCL9 and CXCL10. These discrepencies may be due to differences in mouse strains, reagents, assays and lack of highly purified Treg, since fluorocytometric isolation of CD4+CD25+ cells, which gives the highest purity, results in enrichment but not purification. Ultimately, Treg behavior and properties are in many ways similar to other effector T cells. So far, neither in mice nor in humans has a chemokine receptor been identified that is expressed exclusively by regulatory cells; they are shared by both activated and suppressive lymphocyte populations. The similarity of chemokine-receptor-expression profiles and migration capacity between Treg and effector T cells may be expected since Treg must migrate to sites to closely contact effector T cells or other target cells in order to execute their regulatory effect.

We found the mRNA for most chemokine receptors is expressed at comparable levels in CD4+CD25+ and CD4+CD25− cells, except that CCR6 expression is higher on CD4+CD25+ Treg, while CXCR6 expression is higher on CD4+CD25− cells (16). However, similar chemokine-receptor profiles do not necessarily mean identical receptor usage or chemotatic mechanisms. Treg have similar abilities to migrate to conditioned media (consisting of multiple inflammatory chemokines and cytokines produced by inflamed islets), and their migration is comparable to CD4+CD25− T cells. Blockade of CCR4 and CCR6 partially blocked the migration of both naive T cells and Treg, however blockade of CCL2, CCL5 and CXCR3 inhibited CD4+CD25− T cell but not Treg migration, suggesting that Treg use slightly different but overlapping arrays of chemokine-receptor interactions to migrate to sites of inflammation (16).

Integrins, Selectins and Treg Migration

  1. Top of page
  2. Common Concepts in Leukocyte Trafficking/Migration
  3. Treg Chemokine Receptors and Responses
  4. Integrins, Selectins and Treg Migration
  5. Treg Homeostatic Trafficking To and Within Lymphoid Organs
  6. Other Regulators of Leukocyte Migration and Their Potential Role in Treg Migration
  7. Treg Regulate Migration of Other Leukocytes
  8. Conclusions
  9. Acknowledgments
  10. References

Some integrins have been shown to play important roles in Treg tissue or lymphoid organ homing (Table 2). CD103 is the αE chain of the αEβ7 integrin whose principal ligand is E-cadherin, an epithelial homing adhesion molecule. Expression of CD103 at very high levels is a hallmark of intraepithelial lymphocytes residing in the gut wall and other epithelial compartments, such as the skin and lung (17). Several groups have identified αE as predominantly expressed on CD25+ Treg, suggesting CD103 marks Treg subsets with enhanced regulatory activity compared with their CD103− counterpart (18–20). Huehn et al. identified unique αE+ CD25− murine T-cell populations with suppressive function. They further analyzed αE/CD25-defined Treg subsets and their distinct homing properties: αE− CD25+ Treg preferentially recirculate through lymph nodes, whereas αE+ CD25+ T cells represent inflammation-seeking Treg (21). In contrast, a study from Powrie's group showed no mandatory role for CD103 expression on T cells for either the development or CD4+CD25+ Treg-mediated control of colitis. However, wild-type CD4+CD25+ T cells were unable to prevent colitis in immune-deficient recipients lacking CD103, demonstrating a nonredundant functional role for CD103 on host cells, primarily DC, in Treg cell-mediated intestinal immune regulation (22). Suffia et al. demonstrated in a Leishmania major infection model that CD103 does not define a subset of regulatory T cells with distinct properties, but rather that this molecule is rapidly induced and maintained on Treg following, or just prior to, their arrival in tissues, arguing for a role for CD103 in retention of Treg in inflamed tissues (23).

Table 2.  Integrin, selectin usage by Treg
SpeciesTreg typeIntegrins, selectins involvedModelReference
MouseCD4+CD25+/CD4+CD25−αEβ7/CD103In vitro, colitis18,21
MouseCD4+CD25+αEβ7/CD103In vitro, IBD19,20
MouseCD4+CD25+αEβ7/CD103Colitis22
MouseCD4+CD25+αEβ7/CD103Leishmania major infection23
HumanCD4+CD25+α4β7, α4β1In vitro24
MouseCD4+αE+E/P selectinsSkin DTH25
MouseCD4+CD25+L-selectin/CD62LColitis, cardiac transplant27,28
MouseCD4+CD25+L-selectin/CD62LAutoimmune diabetes29
MouseCD4+CD25+L-selectin/CD62LFibrosarcoma30
MouseCD4+CD25+L-selectin/CD62LGVHD31,32

In contrast to these data from the mouse, Stassen et al. failed to detect significant expression of CD103 on freshly isolated or activated human Treg (24). Nevertheless, α4-integrin associated with different β-chains (β1 vs. β7) was identified as a marker for two distinct subsets of human Treg, and both showed strong suppressive properties for conventional CD4+ T cells in vitro. Since α4β1 and α4β7 are homing receptors for T-cell migration to inflamed tissues and mucosal sites, respectively, the authors postulated that α4β1 Treg migrated to inflamed tissues where they inhibit T-cell responses, and α4β7 Treg migrated to mucosal tissues to counteract autoreactive T cells.

Siegmund et al. analyzed the functional importance of E/P-selectins and Treg localization for in vivo suppressive capacity in a skin inflammation model. They found that αE+ effector/memory-like Tregs from fucosyltransferase VII-deficient animals, which lack E/P-selectin ligands and fail to migrate into inflamed sites, fail to suppress Th1-mediated delayed-type hypersensitivity. Thus, E/P-selectin-dependent migration into inflamed sites may be a prerequisite for the resolution of inflammatory reactions in vivo (25).

L-selectin (CD62L) engagement has long been known to be important for lymphocyte homing to lymph nodes, and also contributes to chemokine-induced leukocyte migration within extravascular tissues both in acute and chronic inflammation (26). Our and others work showed that CD62L is critical in CD4+CD25+ positioning and regulatory function. Previous work in our laboratory showed that while both CD62L+ or CD62L− Treg subsets express Foxp3 and are anergic, the CD62L+ population is more potent on a per-cell basis, and proliferates and maintains suppressive function far better than the CD62L− population and unseparated CD4+CD25+ Treg. The CD62L+ population preferentially migrates to CCL19, CCL2 and FTY720 (27). Recent work in our laboratory showed an expansion of CD4+CD25+CD62L+ T cells specifically within the lymph node (LN) of tolerant allograft recipients, but not in other anatomic sites or under nontolerizing conditions. These cells exhibited a substantial up-regulation of Foxp3 expression, and possessed alloantigen-specific suppressor activity. Neither LN nor other lymphoid cells expressed the regulatory phenotype if recipients were treated with anti-CD62L mAbs, which both prevented LN homing and caused early allograft rejection (28).

Others have reached similar conclusions that the CD62L+ Treg subset is the most immunosuppressive. Treg expressing high CD62L and CCR7 are more potent in suppressing autoimmune diabetes (29). Hiura et al. reported that both regulatory T cells and antitumor effector T cells are primed in the same draining lymph nodes during tumor progression, but only CD62L expression could distinguish regulatory CD4+CD25+ cells from effector CD4+CD25+ cells (30). In a GVHD model, in cotransfer with donor CD4+CD25− T cells, only the CD62L+ subset of CD4+CD25+ Treg cells accumulated in host mesenteric LN and spleen in high number, and prevented severe tissue damage to the colon and protected recipients from lethal GVHD (31). Similarly, another study indicate that CD62Lhi Treg interfere with the activation and expansion of GVHD effector T cells in secondary lymphoid organs early after bone marrow transplantation. Both donor- and host-type CD62Lhi, but not CD62Llo, Treg potently increased donor BM engraftment in sublethally irradiated mice (32).

Treg Homeostatic Trafficking To and Within Lymphoid Organs

  1. Top of page
  2. Common Concepts in Leukocyte Trafficking/Migration
  3. Treg Chemokine Receptors and Responses
  4. Integrins, Selectins and Treg Migration
  5. Treg Homeostatic Trafficking To and Within Lymphoid Organs
  6. Other Regulators of Leukocyte Migration and Their Potential Role in Treg Migration
  7. Treg Regulate Migration of Other Leukocytes
  8. Conclusions
  9. Acknowledgments
  10. References

Peripheral T cell homeostatic trafficking, or trafficking during noninflammatory conditions, to lymphoid organs is mediated by CCL19, CCL21/CCR7 and CXCL12/CXCR4 (Table 3) (33). Treg have been reported to express CCR7, respond to lymphoid chemokines CCL19 and CCL21, and home to secondary lymphoid organs (6,27). Conversely, it was also reported that CD4+CD25+ regulatory T cells were hyporesponsive to CCL21-induced migration, and unresponsive to CCL21 costimulation, in contrast to their effector T cell counterparts (34). Treg are likely heterogeneous since Szanya et al. demonstrated that CD4+CD25+ suppressor T cells are comprised of at least two subpopulations that express distinct chemokine-receptors and chemotactic-response profiles. CD4+CD25+CD62L+ Treg express CCR7 at high levels and migrate toward CCL19, whereas CD4+CD25+CD62L− Treg preferentially express CCR2, CCR4 and CXCR3 and migrate toward the corresponding chemokines (CXCL9, CXCL10, CCL17 and CCL22) (29). Valmori et al. identified a distinct subset of human CD4+CD25+ Treg contained in the CD45RA+/RO− naive fraction expressing the CCR7+CD62L+CTLA-4+FOXP3+ phenotype, which they designate as natural naive Treg. This subset is prominent in young adults and decreases with age (35).

Table 3.  Chemotactic molecules usage associated with Treg trafficking to and within lymphoid organ
SpeciesTreg typeChemokines, selectins involvedAssociated Treg activityReference
HumanCD4+CD25+CCR7/CCL19,21Homeostatic to LN6
MouseCD4+CD25+CCR7/CCL19,21Homeostatic to LN27,34
MouseCD4+CD25+CD62L+CCR7/CCL19To LN29
HumanCD4+CD25+CCR7+CD62L+Mature naïve Treg35
MouseCD4+CD25+CCR7/CCL19, CXCR5/CXCL13Within tonsil38
HumanCD4+CD25+CXCR4/CXCL12To bone marrow39

How Treg traffic inside lymphoid organs, position themselves from one microdomain to another within secondary lymphoid organs and interact with APC and effector T cells or B cells may be critical aspects of Treg function and tolerance. A recent study by Tang et al. analyzed Treg, T effector cell and DC interactions within lymph nodes during priming of diabetogenic T cells using two-photon laser-scanning microscopy. They did not find detectable stable association between Treg and Th cells during active suppression. In contrast, direct interaction between Treg and islet-antigen-bearing DC was identified, preceding the inhibition of Th cell activation. This study suggests that –DC–Treg interactions inside lymph nodes are central to Treg function in vivo (36). It has also been shown that Treg capable of migrating to the LN, but incapable of migrating to the intestine, can still inhibit colitis (37). Yet how Treg traffic inside lymphoid organs is poorly understood. Lim et al. (38) found that human tonsilar CD4+CD25+CD69− Treg migrate well to CCL19 (CCR7 ligand), expressed in the T-cell zone, but poorly to CXCL13 (CXCR5 ligand), expressed in the B-cell zone. Upon T-cell activation, these cells rapidly change their chemotactic behavior to traffic toward B-cell follicles, and this change is coincident with a switch in chemokine-receptor expression from CCR7 to CXCR5. The authors further showed that tonsilar Treg suppress germinal center T helper cells and T-cell-induced B-cell responses, such as Ig production, survival and expression of activation-induced cytosine deaminase.

Zou et al. (39) showed that CXCL12 is expressed in bone marrow and induces Treg chemotaxis and adhesion/transmigration; G-CSF mobilizes human bone marrow Treg through reducing marrow-derived CXCL12; human Treg preferentially home to bone marrow but not to spleen under homeostatic conditions in NOD/SCID mice; and blocking CXCL12/CXCR4 signals significantly reduced Treg trafficking to bone marrow. Therefore, as a primary lymphoid organ, bone marrow is a significant reservoir for human Treg, and Treg trafficking between the bone marrow and periphery is mediated by CXCL12/CXCR4 signals.

Other Regulators of Leukocyte Migration and Their Potential Role in Treg Migration

  1. Top of page
  2. Common Concepts in Leukocyte Trafficking/Migration
  3. Treg Chemokine Receptors and Responses
  4. Integrins, Selectins and Treg Migration
  5. Treg Homeostatic Trafficking To and Within Lymphoid Organs
  6. Other Regulators of Leukocyte Migration and Their Potential Role in Treg Migration
  7. Treg Regulate Migration of Other Leukocytes
  8. Conclusions
  9. Acknowledgments
  10. References

Regulators of G-protein signaling (RGS) are a group of proteins that enhance the deactivation of Gα subunits, thereby reducing the activation of downstream effectors (40). Since chemokines guide leukocyte migration through G-protein-coupled receptors, the level and regulation of RGS protein in lymphocytes likely significantly impact lymphocyte migration and function. Lymphoid cells have been found to express various RGS molecules (41). Agenes et al. found an inverse correlation between the capacity to migrate and the levels of RGS1, RGS9 and RGS16 for both naïve and regulatory T cells. They showed that in parabiotic mice naïve T cells migrated much more than Treg and expressed low levels of these RGSs. RGSs are expressed at even lower levels on migrated naïve T cells. In contrast, activated cells and Treg expressed higher levels of these RGSs, suggesting that up-regulation of RGS in Treg desensitizes their chemokine receptors and limits their migration (42).

Treg Regulate Migration of Other Leukocytes

  1. Top of page
  2. Common Concepts in Leukocyte Trafficking/Migration
  3. Treg Chemokine Receptors and Responses
  4. Integrins, Selectins and Treg Migration
  5. Treg Homeostatic Trafficking To and Within Lymphoid Organs
  6. Other Regulators of Leukocyte Migration and Their Potential Role in Treg Migration
  7. Treg Regulate Migration of Other Leukocytes
  8. Conclusions
  9. Acknowledgments
  10. References

Treg have been shown to impact almost every aspect of effector T-cell function, including the earliest stages of T-cell activation, activation marker expression, IL-2 production, proliferation and the increase in cell size associated with activation. Trafficking is also a basic aspect of T-cell function, but how Treg affect effector T-cell trafficking is rarely studied. Using a T-cell receptor (TCR) transgenic model of diabetes, Sarween et al. showed that CD4+CD25+ Treg modestly inhibit CD4 cell expansion, but potently suppress tissue infiltration. This was associated with a failure of CD4 cells to differentiate into effector cells and to up-regulate IFN-γ-dependent CXCR3, which confers the ability to respond to pancreatic islet derived CXCL10. This study suggested that Treg permit T-cell activation, but prohibit their differentiation and migration into antigen bearing tissue (43).

There are similar reports of inhibition of effector T-cell migration by other regulatory T cells or anergic T cells. Chen et al. showed in an autoimmune diabetes model that autoantigen-specific (tetramer+) Th2 and Tr1 cells could block diabetogenic T-cell migration into lymph nodes (44). James et al. reported that both murine and human anergic T cells impair the ability of parenchymal cells, including endothelial and epithelial cells, to establish cell–cell interactions necessary to sustain leukocyte migration in vitro and tissue infiltration in vivo (45). Furthermore, the same group reported that anergic T cells can inhibit migration of responsive T cells in an antigen-independent manner both in vitro and ex vivo, by an anti-inflammatory mechanism involving enhanced dipeptidyl-peptidase enzymatic activity (46).

Conclusions

  1. Top of page
  2. Common Concepts in Leukocyte Trafficking/Migration
  3. Treg Chemokine Receptors and Responses
  4. Integrins, Selectins and Treg Migration
  5. Treg Homeostatic Trafficking To and Within Lymphoid Organs
  6. Other Regulators of Leukocyte Migration and Their Potential Role in Treg Migration
  7. Treg Regulate Migration of Other Leukocytes
  8. Conclusions
  9. Acknowledgments
  10. References

Overall, the current knowledge about Treg migration is still limited. An important message from the studies is that the migration behavior of Treg crucially influences their suppressive activity in vivo, and subsets of Treg differing in chemokine receptors, selectins or integrin expression possess different functional potentials in peripheral tolerance induction and maintenance. Areas requiring further investigation include where, when and how Treg exert their function, what are the determinants of Treg trafficking and function. Whether and how Treg modulate the migration of other T cells is an emerging field of interest. Understanding Treg migration will undoubtedly lead to a better understanding of mechanism of Treg function and new possibilities for immunotherapy.

References

  1. Top of page
  2. Common Concepts in Leukocyte Trafficking/Migration
  3. Treg Chemokine Receptors and Responses
  4. Integrins, Selectins and Treg Migration
  5. Treg Homeostatic Trafficking To and Within Lymphoid Organs
  6. Other Regulators of Leukocyte Migration and Their Potential Role in Treg Migration
  7. Treg Regulate Migration of Other Leukocytes
  8. Conclusions
  9. Acknowledgments
  10. References
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