Th1Th2 Cells

A major challenge in understanding the roles of chemokine receptors on lymphocytes is to discover the organizing principles that determine patterns of chemokine receptor expression. The TCM/TEM paradigm provides a basis for understanding the pattern of CCR7 expression. Although other chemokine receptors show non-uniform expression when analyzed on TCM versus TEM subsets, this paradigm cannot provide a framework that is sufficiently informative for explaining the complexity of chemokine receptor expression on T cells. With regard to CD4+ T cells, the Th1/Th2 paradigm is also clearly relevant. A variety of chemokine receptors have been reported to be expressed differentially on Th1 versus Th2 cells (48,58-64). Although some reports suggest preferential expression of CCR7 on Th1 cells (65), most investigators have reported no specific association between CCR7 and Th phenotype (31,34).

Several groups have reported the preferential expression of CXCR3 and CCR5, as well as CCR2, on Th1 cells, with the strongest and most consistent relationship shown for CXCR3 (34,48,52,64,66-73). The association of CXCR3 with the Th1 phenotype is consistent with the strong induction of CXCR3 ligands, CXCL9-11, by IFN-y. The expression of CXCR3 on Th1 T cells is dependent on the presence of IFN-y. Activated T cells from mice deficient in IFN-y are unable to express CXCR3 and fail to migrate to CXCL9-11 (73). There are data indicating that CCR5 and CCR2 expression is not independently associated with the Th1 phenotype, but that the association is due to coexpres-sion of CXCR3 on a high proportion of CCR5+ and CCR2+ cells (71). However, CCR5 has been reported to be induced by IL-12 on activated T cells (74,75), and to be a target gene of T-bet (76), the driving cytokine and transcription factor, respectively, for Th1 differentiation. Whatever the strength of the association between Th1 polarization and CCR5, CCR5-null (CCR5532) humans are able to mount a productive Th1 phenotype immune response, with normal levels of IFN-y produced from T cells (77). Consistent with the observations above, both CXCR3 and CCR5 have been found to be highly expressed in inflammatory diseases and tissues associated with type 1 responses (78).

CCR4 and CCR8 have been described as receptors preferentially expressed on Th2 cells (58,69,72,79,80). Just as for the Th1-associated chemokine receptors, despite the strong preferential association of CCR4 and CCR8 with Th2 cells, there is no evidence that these Th2-associated receptors are necessary for Th2 cell polarization (60,81).

7.3.4. Regulatory T Cells

There has been a great deal of recent interest in a subset of CD4+ regulatory T cells (Tregs) that depend for their production on the transcription factor FoxP3 and that are characterized by high surface expression of CD25 (reviewed in Ref. 82). Tregs inhibit the activation of T cells and innate immune cells, apparently to suppress autoimmunity. To modulate responses in the periphery, Tregs must home to the site of inflammation, and Tregs have been shown to express a variety of chemokine receptors that would serve this function, including CCR4, CCR5, CCR6, and CCR8 (83-86). Consistent with a role for these chemokine receptors in Tregs function, deficiency of CCR5 on these cells exacerbated experimental graft versus host disease (85) in mice. Chemokine receptors important in defining and characterizing pathways of T-cell differentiation are listed in Table 1.

7.3.5. Effector B Cells

Like memory/effector T cells, effector B cells (i.e., plasmablasts/plasma cells) depend on chemokine receptors for their migration and positioning. B-cell differentiation into plasma cells is associated with downregulation of CCR7 and CXCR5 and increased responsiveness to the CXCR4 ligand, CXCL12, which has been shown to be important for proper localization of plasma cells in spleen and bone marrow (87). Subsets of memory B cells, plasmablasts, and plasma cells have been reported to depend on particular chemokine receptors analogous to effector/memory T-cell subsets. CXCR3 is induced on memory B cells and plasma cells in response to IFN-y and is found preferentially on cells expressing IgG1 (88). CCR9 and CCR10 have been found on cells producing IgA, consistent with the trafficking of these cells to mucosal sites (89-91) (see below). Both CCR9 and CCR10 have been shown to be important for trafficking of IgA-producing cells to the small intestine, whereas only CCR10 is important for these cells' trafficking to the colon (92), and CCR10 has been shown to be important for the accumulation of IgA plasma cells in the lactating

Table 1

Chemokine Receptors on Memory T-Cell Subsets

Table 1

Chemokine Receptors on Memory T-Cell Subsets

Cell types

Receptors

Roles

Early memory cells

CXCR3, CCR4

Used to identify these cells, which have an otherwise naive phenotype

Central memory (TCM)

CCR7

Used to define these cells and allows entry into secondary lymphoid organs

Effector memory (TEM)

CCR7 (absent)

Lack CCR7 and are thereby excluded from noninflamed secondary lymphoid organs

T helper 1 (Th1)

CXCR3, CCR5

Th1 cells are a subset of CXCR3+ cells

T helper 2 (Th2)

CCR4, CCR8

Th2 cells are a subset of CCR4+ cells

Regulatory T (Treg)

CCR4, CCR5, CCR6, CCR8

Tregs found in CCR4+CCR5+ subset

mammary gland (90). Memory B cells produced during the response to rotavirus, an intestinal pathogen, have been reported to lose CCR9 and CCR10 and upregulate CCR6, which has been postulated to mediate a switch from gut-specific trafficking to widespread dissemination to mucosal sites (91).

7.3.6. T Cells Homing to Skin

For memory/effector T cells, just as described above for naïve T cells and implied in the discussion of B-cell trafficking, some chemokine/receptor groups are dedicated to compartment-specific recruitment. The skin and the gut represent dichotomous compartments that have been intensively studied with regard to trafficking of memory lymphocytes, and cells specific for those compartments express cutaneous lymphocyte antigen (CLA) and the integrin a4p7, respectively (reviewed in Ref. 93). The majority of skin-homing lymphocytes express CCR4 and to a lesser extent CCR10 (94-96). CCL17 thymus and activation-regulated chemokine (TARC), a ligand for CCR4, is expressed by cutaneous endothelial cells and keratinocytes in the skin, and this expression is enhanced by IFN-y and TNF-a (94,97,98). CCL27, a ligand for CCR10, is expressed by keratinocytes and is upregulated by proinflammatory cytokines (95,97,99). Intradermal injections of CCL27 can induce the migration of CCR10+ CLA+ T cells to the skin (95), and anti-CCL27 has been reported to diminish contact hypersensitivity in mice (95). Mice deficient in CCR4 also have decreased numbers of E-selectin ligand (CLA)+ T cells, which suggests that CCR4 is required for the development and/or survival of skin-homing T

cells (100). Also in mouse studies, recruitment to inflamed skin could be supported by either CCR4 or CCR10 (94), although data on expression of CCR4 and CCR10 on CD4+ T cells in inflamed human skin suggest a dominant role for CCR4, as only a small percentage of cells express CCR10 (96).

7.3.7. T Cells Homing to Gut/Mucosa

With regard to the gut, CCR9 is the best-described receptor involved in the migration of T cells specifically to this compartment, and within the gut, preferentially to the small bowel (101). CCR9 has been shown to be important but not indispensable for development of small intestine intraepithelial lymphocytes (10,102-104), as well as for recruitment to the small bowel of T cells activated in the mesenteric lymph nodes (105). For the T cells activated in the mesenteric lymph nodes, it has been shown that dendritic cells from Peyer's patches provide the information to induce CCR9 and the a4p7 integrin, thereby imprinting those T cells to traffic to the gut (106). The second chemokine receptor with a specific role in the gut is CCR10, as described above for B cells. Regarding gut T cells, however, CCR10 is remarkable for its absence (89). Thus, although CCR10 is important for trafficking of T cells to skin and of B cells to mucosal sites including the intestine, this receptor seems to have no role in T-cell trafficking to gut. Chemokine receptors important in tissue- and/or compartment-specific migration are listed in Table 2.

Table 2

Chemokine and Sphingosine-1-phosphate Receptors in Tissue-Specific

Lymphocyte Migration

Table 2

Chemokine and Sphingosine-1-phosphate Receptors in Tissue-Specific

Lymphocyte Migration

Organs

Receptors

Roles

Thymus

CXCR4

Progenitor entry and/or localization of DN

thymocytes

CCR9

Progenitor entry and/or DP thymocytes'

migration to cortex

CCR7

Egress by mature cells

S1P]

Egress by mature cells

Bone marrow

CXCR4

B-cell lymphopoiesis

Secondary lymphoid organs

CCR7

Entry and localization in T-cell zones

CXCR5

Organization of B-cell follicles

S1P1

Egress

Skin

CCR4

Homing of effector/memory T-cells

CCR10

Homing of effector/memory/T-cells

Gut

CCR9

Homing of memory T and B cells

CCR10

Homing of IgA-secreting plasma cells

Traditional Chinese Medicine

Traditional Chinese Medicine

Ever wondered what Chinese medicine is all about and whether it works? Thinking about consulting a practitioner but want to know some facts first? Look no further! Here's your chance to purchase an in depth and fully comprehensive eBook on anything and everything to do with this ancient philosophy.

Get My Free Ebook


Post a comment