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(Journal of Leukocyte Biology. 2002;72:1-8.)
© 2002 by Society for Leukocyte Biology

Systemic immunoregulatory and pathogenic functions of homeostatic chemokine receptors

Gerd Müller*, Uta E. Höpken*, Harald Stein{dagger} and Martin Lipp*

* Department of Molecular Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany; and
{dagger} Institute of Pathology, Klinikum Benjamin Franklin, Free University, Berlin, Germany

Correspondence: Dr. Martin Lipp, Department of Molecular Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Strasse 10, 13092 Berlin, Germany. E-mail: mlipp{at}mdc-berlin.de


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ABSTRACT
 
The adoptive immune response relies on a precise temporal and spatial positioning of lymphocytes within lymphoid and nonlymphoid tissues. Chemokines, constitutively expressed or induced during inflammation provide a flexible navigation system directing lymphocytes into specific microcompartments. Precision and specificity in this process are achieved by varying patterns of chemokine receptors expressed on the cell surface of lymphocytes in the course of cell differentiation. The chemokine receptors CXCR5 and CCR7 are principal regulators for targeting T cells, B cells, and dendritic cells into secondary lymphoid organs. The analyses of knockout mice have been instrumental in exploring the crucial role of these receptors for the compartmentalization of secondary lymphoid organs into functionally separated T and B cell zones. Aside from the homeostatic recirculation of lymphocytes and inflammatory processes, chemokine receptors are also involved in malignancies such as lymphoproliferative diseases and cancer metastasis. Recent results from our laboratory present evidence for the involvement of CCR7 in the dissemination of neoplastic cells in classic Hodgkin disease. There is also accumulating evidence for the involvement of CXCR5 in the formation of ectopic follicles as observed in lymphomas or autoimmune diseases. In addition, CCR7 and CXCR5 have been identified as useful markers in the classification of functionally distinct subsets of T-helper cells, which will lead to a better understanding of T cell memory and T cell effector function in lymphoid system homeostasis and disease.

Key Words: CCR7 • CXCR5 • Hodgkin disease • lymphoid organogenesis • memory T cells


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LYMPHOCYTES AT THE GATE—LYMPHOID ORGAN ENTRY
 
Chemokine receptors allow lymphocytes to sense gradients of chemotactic cytokines, thereby directing these cells into specific compartments within lymphoid and nonlymphoid tissues. Cell migration along a chemokine gradient is accompanied by cell polarization, rearrangements of the cytoskeleton, and adhesive interactions with the extracellular matrix [1 ]. Lymphocytes seem to distinguish between multiple overlaying gradients of different chemokines, thus enabling the cells to migrate sequentially along these gradients [2 ]. The precise positioning of cells may also be accomplished by the relative responsiveness to chemokines expressed in separate but adjacent zones [3 ]. Besides navigating lymphocytes within tissues, chemokines are important regulators for the extravasation of lymphocytes from the bloodstream in high endothelial venules (HEVs) of secondary lymphoid organs. Lymphocyte extravasation is a multistep process involving several families of adhesion molecules such as selectins, integrins, and members of the immunoglobulin (Ig) superfamilies [4 ]. In this connection, chemokines presented on the luminal surface of the endothelium trigger the activation of integrins on the cell surface of rolling lymphocytes. Activated integrins mediate a tight adhesion of the lymphocytes to the endothelial cells, a prerequisite for the diapedesis through the endothelial cell layer into the underlying tissue.


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FUNCTIONAL POSITIONING OF B AND T CELLS
 
Once released from primary lymphoid organs, naïve antigen inexperienced lymphocytes recirculate through secondary lymphoid organs in order to encounter their cognate antigen (Fig. 1 ). In lymph nodes, for instance, naive T cells and B cells extravasate from the bloodstream through a specialized endothelial cell layer in HEVs. They enter the T cell rich zone of a lymph node where dendritic cells (DCs) act as professional antigen presenting cells (APCs). Only T cells that successfully scan APCs for a matching antigen become activated and start to proliferate. Otherwise, they leave the lymph node by the efferent lymphatics and continue to recirculate through secondary lymphoid tissues. Naive B cells follow the same route as T cells but proceed to migrate into B cell follicles. Priming of B cells with the antigen can occur almost anywhere along their route to the B cell area of lymph nodes. Activated T cells and antigen-primed B cells meet each other at the edge of B cell follicles where the CD40-dependent B cell activation by T cells occurs. The differentiation of activated B cells into Ig-secreting plasma cells within B cell follicles leads to the formation of germinal centers (GCs) where isotype switching and affinity maturation occur. On this occasion, B cells require the presence of antigen-primed CD4+ T-helper (Th) cells within the B cell follicle to spur on the GC reaction.



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  		Figure 1. Model of chemokine-directed trafficking of lymphocytes and DCs to and through secondary lymphoid organs during the immune response. Once resident DCs in peripheral tissues become activated, they start to maturate and migrate into the draining lymph nodes via the lymphatic system. During maturation, antigen-capturing DCs differentiate into antigen-presenting DCs highly expressing CCR7. Upon immigration, these cells populate the T cell areas of secondary lymphoid organs. In contrast, B cells and naïve T cells enter lymph nodes through HEVs. Chemokines such as CCL19 and CCL21, ligands for the chemokine receptor CCR7, which are produced by the endothelial cells of the HEVs or transcytosed to the luminal surface, enable lymphocytes to cross the endothelial cell layer and enter the T cell zone of the lymph node [5 , 6 ]. CCL19 produced by mature, interdigitating DCs (iDCs) facilitates the scanning of iDCs by naïve T cells in search of their cognate antigen. In contrast, B cells expressing CXCR5 migrate through the T cell zone into B cell follicles where CXCL13, the ligand for CXCR5, is produced by follicular stromal cells. B cells becoming activated by T cells may start to proliferate in the follicle, giving rise to the formation of a GC. Activated T cells expressing CXCR5 may also enter the follicle to participate in the GC reaction. B cells and T cells, which do not become activated, leave the secondary lymphoid organ by the efferent lymphatics. LC, Langerhans cell; MZ, mantle zone.


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CCR7 AND CXCR5 GUIDE LYMPHOCYTES IN SECONDARY LYMPHOID ORGANS—LESSONS FROM KNOCKOUT MICE
 
CCR7 is the major homing receptor directing T lymphocytes, B lymphocytes, and DCs into the T cell areas of secondary lymphoid organs. CCL19 (also called ELC or MIP-3ß) and CCL21 (also called SLC or 6Ckine), both ligands for CCR7, are expressed constitutively within the T cell zone of peripheral lymph nodes, Peyer’s patches, and the spleen. In addition, CCL21 is expressed by the endothelial cell layer of HEVs within Peyer’s patches and peripheral lymph nodes [7 8 9 10 11 12 ]. Expression of neither CCL19 nor CCL21 can be detected within B cell follicles of secondary lymphoid organs. The impaired migration of lymphocytes and DCs in CCR7 knockout mice causes an increased number of T cells in peripheral blood, a profound disorganization of secondary lymphoid tissues, a significant delay in mounting antibody responses, and a lack of contact sensitivity and delayed-type hypersensitivity reactions [13 ]. This phenotype closely resembles that of plt (paucity of lymph node T cells) mice, which fail to express CCL21 by the endothelial cells of HEVs [14 ]. However, the migration of DCs and B cells is less affected in plt mice.

Expression of CXCR5 is restricted to mature, recirculating B cells as well as small subpopulations of CD4+ and CD8+ T lymphocytes [15 ]. The only known ligand for CXCR5, CXCL13 (BCA-1/BLC), is expressed constitutively within B cell follicles of secondary lymphoid organs, most probably by follicular stromal cells [16 17 18 ]. CXCR5 as well as CXCL13 knockout mice exhibit a quite similar phenotype. Both knockout mice lack most peripheral lymph nodes and show a reduced number of Peyer’s patches. Moreover, the architecture of primary lymphoid follicles in the spleen is disorganized [19 , 20 ]. Because of the absence of several peripheral lymph nodes and a reduced number of Peyer’s patches in CXCR5 knockout mice, it was tempting to speculate that this receptor is not only involved in immune-system homeostasis but also in lymphoid organogenesis.


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CHEMOKINES ARE INVOLVED IN SECONDARY LYMPHOID ORGAN ORGANOGENESIS
 
In addition to its chemotactic activity on CXCR5 expressing B and T cells, CXCL13 has been shown to induce the expression of lymphotoxin (LT)-{alpha}1ß2 in resting B cells [20 ]. In turn, LT-{alpha}1ß2 induces follicular DC (FDC) development, thereby promoting the expression of CXCL13 [17 ]. This mutual interaction between B cells and FDCs in B cell follicles of secondary lymphoid organs is also effective in Peyer’s patches organogenesis, a multistep process depending on the interaction of intestinal mesenchymal cells and lymphoid cells expressing the interleukin-7 receptor {alpha} (IL-7R{alpha}) [21 , 22 ]. Peyer’s patches inducing-lymphoid cells stimulated through the IL-7R{alpha} express LT-{alpha}1ß2, which in turn induces the expression of CXCL13 and several adhesion molecules by mesenchymal cells [21 , 23 ]. CXCL13 secreted by the mesenchymal cells may then attract additional Peyer’s patches-inducing lymphoid cells, which are known to express CXCR5, thereby leading to the formation of Peyer’s patches anlagen. Since LT-{alpha}1ß2 promotes the secretion of CXCL13 on resting B cells in vitro, this might also be true for the CXCR5 expressing Peyer’s patches-inducing lymphoid cells, thus establishing a positive feedback loop. Later, following the formation of HEVs in Peyer’s patches organogenesis, CXCL13 may also contribute to the colonization of the Peyer’s patches anlagen by B and T cells.


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HOMEOSTATIC CHEMOKINES IN NEOPLASIA
 
Chemokines can be broadly divided into two categories: i) those being expressed constitutively are involved in the lymphoid system homeostasis, thereby forming the architecture of secondary lymphoid organs (Table 1 ), and ii) inducible chemokines that are expressed during inflammation in order to recruit lymphocytes at the site of inflammation. It must be emphasized that constitutive and inducible expression of chemokines are simplified categories, since the expression levels of many so-called constitutively expressed chemokines are regulated in the course of cell activation and differentiation [24 ]. Nevertheless, this concept conveys an idea of how chemokines may act in disease. The expression of inducible chemokines out of time and place may lead to an inappropriate infiltration of the tissue with leukocytes expressing the corresponding chemokine receptors. In comparison, constitutively expressed chemokines within secondary lymphoid organs may take responsibility for the invasion of these organs by neoplastic and accessory cells.


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  		Table 1. Chemokines Involved in Lymphoid System Homeostasis

A recent report emphasizes that the chemokine receptor CXCR4 and its ligand CXCL12, belonging to the group of homeostatic chemokines, are critically involved in the metastasis of breast cancer [25 ]. There is also strong evidence for a participation of CCR7 in this process. Both receptors can be detected on breast cancer cells, while their corresponding ligands are commonly expressed in organs representing typical destinations in metastasis formation. Cellular responses associated with migration, chemotaxis, and invasion have been demonstrated for both chemokine receptors on breast cancer cells in vitro. In addition, inhibition of the interaction of CXCR4 and CXCL12 leads to a significant decrease in metastasis. Other examples of tumor entities of hematopoietic origin expressing functionally active CXCR4 are acute myeloid and lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin B cell lymphoma [26 27 28 29 ].

CCR7 and CXCR5 are of particular interest in lymphoproliferative diseases involving secondary lymphoid organs. CCR7 has been implicated in the course of adult T cell leukemia (ATL), since high expression levels of CCR7 on ATL cells correlate with a high probability of lymphoid organ infiltration [30 ]. CXCR5 may be involved in diseases associated with the formation of ectopic lymphoid follicles such as gastric lymphomas, Sjögren’s syndrome, Hashimoto’s thyroiditis, and autoimmune diabetes. Checking for the expression of chemokines in mucosa-associated lymph tissue (MALT) lymphomas, we detected high levels of CXCL13 but also CCL19 and CXCL12 by immunohistochemistry on frozen tissue sections (Fig. 2 ). These results are in agreement with published data showing that CXCL13 is highly expressed in Helicobacter pylori-induced, mucosa-associated lymphoid tissue and gastric lymphoma [31 ]. In comparison, expression of CCL21 was restricted almost exclusively to endothelial cells within the neoplastic tissue in gastric lymphoma. It is interesting that ectopic expression of the chemokines CCL21 and CXCL13 in pancreatic islets tested to be sufficient for the induction of lymphoid neogenesis [32 , 33 ]. The recruitment of lymphocytes and DCs leads to a spontaneous organization of lymphoid tissue including the compartmentalization in B and T cell zones, HEVs, and stromal cells. As CXCL13 is also an efficient activator of the mitogen-activated protein kinase signaling pathway [34 ], it would be interesting to test for a possible proliferative signal supplied by CXCL13, not only in lymphoid system homeostasis but also during the formation of ectopic lymphoid tissues and for tumor cells expressing CXCR5.



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  		Figure 2. Expression of chemokines in MALT lymphoma. Frozen tissue sections were stained with antibodies for the chemokines indicated or a control antibody.


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THE IMPACT OF CCR7 ON TUMOR CELL DISSEMINATION IN HODGKIN’S DISEASE (HD)
 
HD comprises a group of lymphomas characterized by the presence of neoplastic Reed-Sternberg cells and their variant forms most commonly located within lymphoid tissue. The lineage origin of multinucleated Reed Sternberg cells and their single nucleated variants are still under debate. However, there is accumulating evidence for a B cell origin of Hodgkin-Reed Sternberg (HRS) cells in the common classic HD (cHD) and the malignant lymphocytic and histiocytic (L&H) cells in the rare nodular lymphocyte predominant HD (NLPHD). The neoplastic cells in HD are characteristically present in a background of reactive cells (lymphocytes, eosinophils, plasma cells, and histiocytes), which usually far outnumber the neoplastic cells. HD is associated with an abnormal cytokine production including LT-{alpha} and tumor necrosis factor {alpha}, cytokines known to induce the expression of constitutively expressed chemokines within lymphoid tissues [17 ]. Several studies suggest the involvement of chemokines such as CCL17 and CCL22 in the accumulation of lymphocytes in HD. It has also been shown that HRS cells induce fibroblasts to secrete CCL11, thereby attracting eosinophils into the HD tissue [35 ]. The localization of HD within lymph nodes and the elevated expression levels of cytokines, which are known to be involved in the secretion of CCL19, CCL21, and CXCL13, prompted us to test for the involvement of CCR7 and CXCR5 in HD [36 ]. Investigation of receptor expression by immunohistology on paraffin sections revealed a striking difference between the entities of cHD and the rare NLPHD. Tumor cells in NLPHD, L&H cells, frequently reside within follicular structures. They highly express CXCR4 but not CCR7, with CXCR5 being difficult to evaluate due to the generally strong signal for CXCR5 within the tumor nodules (Fig. 3A ). In contrast, neoplastic cells in cHD are located mainly within the interfollicular zone in lymph nodes. They express high levels of CCR7 and CXCR4 but variable levels of CXCR5 (Fig. 3B) . Conforming to the staining patterns of CCR7, expression of CCL19 (Fig. 3D) and CCL21 by reactive cells could be demonstrated in tumor infiltrates in the vast majority of cHD cases. In contrast, CCL19 (Fig. 3C) and CCL21 were found in the internodular areas in NLPHD, whereas tumor nodules were almost devoid of both chemokines. The staining pattern for CXCL12 resembled that of CCL19 and CCL21. CXCL13 was strongly expressed within the follicles of NLPHD and, interestingly, by reactive cells in many cases of cHD. Functional activity of the chemokine receptors could be demonstrated in vitro by using a panel of HD-derived cell lines in chemotaxis assays.



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  		Figure 3. CCR7 expression in HD. (A and B) Immunohistochemical detection on paraffin-embedded sections using the 3D12/CCR7 monoclonal antibody. The neoplastic cells in NLPHD (arrowheads) are completely negative for CCR7 (A), whereas the neoplastic cells of cHD are strongly positive for CCR7 (B). (C and D) Radioactive in situ hybridization with a probe specific for ELC transcripts. The nodules in NLPHD are negative for ELC, but ELC-specific signals are observed in the internodular areas of the nodules (C). In cHD, reactive cells within the tumor infiltrate express ELC (D). All chemokines are expressed in the nonneoplastic leukocytic infiltrates of HD but not in the HRS cells (arrows). Original magnification, x20 (C) and x200 (A, B, D).

The distinct expression patterns for CXCR5 and CCR7 observed on primary HRS cells, L&H cells and of HD cell lines may be explained by the activity of a small set of transcription factors in these cells. High expression of CCR7 on HRS cells in cHD and HD cell lines, but not on L&H cells from NLPHD, appears to be the consequence of a constitutive nuclear factor (NF)-{kappa}B activity, which is frequently observed in HRS cells and HD cell lines [37 ]. In line with these results, inhibition of constitutive NF-{kappa}B activity by the superrepressor I{kappa}B{Delta}N significantly reduces the mRNA level for CCR7 in HD cell lines [36 ]. Signaling via the lymphocyte activation antigen CD30, detectable on HRS cells but not L&H cells, induces the expression of CCR7 mRNA and may therefore be involved in the NF-{kappa}B-dependent expression of CCR7 in HD [37 ]. Although NF-{kappa}B is known to direct the B cell-specific expression of CXCR5 in combination with the transcription factor Oct2 and its coactivator Bob1 [38 ], CXCR5 is only variably expressed on HRS cells with low abundance. This probably results from the defective expression of Oct2 and Bob1, which can be observed frequently in HRS cells but not in lymphocyte-predominant HD [39 , 40 ].


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CHEMOKINES DRIVE THE DEVELOPMENT OF ECTOPIC FOLLICLES
 
In rheumatoid arthritis (RA) monocytes, B cells, and large numbers of CD4+ memory T cells infiltrate and accumulate in the synovium. A particular feature of RA is the high degree of organization of lymphocytes within the inflamed synovium. A rheumatoid lesion is often associated with the development of follicle-like structures yet lacking a clear B cell/T cell segregation [41 ]. However, the centers of these structures are often devoid of T cells, harboring instead a perivascular network of FDCs in which B cells proliferate [42 ]. In RA, lymphocytes appear to be activated, but their precise role in the cellular pathogenic mechanisms and structural requirements permitting the generation of tertiary lymphoid tissue is largely unknown. Recently, CXCL13 and LT-ß were described as predictors for the recruitment of FDCs and the formation of GCs in RA [43 ]. Both factors appeared to be necessary but not sufficient for GC formation. It is interesting that CXCL13 and LT-ß were classified as independent variables in the prediction of GC-positive synovitis. Therefore, they should at least partially compensate for each other in GC formation. In line with this observation is the finding that GC formation can occur in the absence of CXCL13/CXCR5 in CXCL13 and CXCR5 knockout mice, although the GCs are usually misplaced and smaller compared with GCs in wild-type mice [20 , 44 ]. Moreover, expression of LT-{alpha}1ß2 was shown to be independent of CXCL13 in GC B cells of CXCL13 knockout mice [20 ]. Nevertheless, declaring CXCL13 and LT-ß as independent factors contrasts the requirement of LT-{alpha}1ß2 in the formation of GC-FDC networks [45 , 46 ]. In order to reveal the precise function of CXCL13 and other chemokines in lymphoid neogenesis, the cellular sources of these molecules in ectopic lymphoid tissue remain to be identified.


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CXCL13 IS REQUIRED FOR B-1 CELL HOMING
 
In contrast to the conventional B cells (also termed B-2 cells), B-1 cells preferentially home to the peritoneal and pleural cavity. They are involved in thymus-independent antigen responses and represent a major source of natural antibodies. B-1 cells usually do not contain somatic mutations in their Ig genes and mainly produce low-affinity IgM for common bacterial and self-antigens. In addition to their role in natural immunity, they appear to be associated with several autoimmune diseases [47 ]. CXCL13 knockout mice show a severe reduction in the number of B-1 cells in the peritoneal and pleural cavities where CXCL13 is expressed constitutively by macrophages and cells of nonhematopoietic origin [48 ]. Since levels of natural antibodies in unimmunized mice as well as the production of antibodies following intraperitoneal immunization with a thymus-independent antigen are reduced markedly in these knockout mice, CXCL13 appears to be a critical factor in B-1 cell homing.

In the context of murine lupus in NZB/W mice, a mouse model for systemic lupus erythematosus, the aberrant expression of CXCL13 by myeloid DCs leads to the accumulation of B-1 cells within the target organs as reflected by an elevated ratio of B-1 to B-2 cells [49 ]. The preferential attraction of B-1 over B-2 cells might be the consequence of higher expression levels of CXCR5 on B-1 compared with B-2 cells. However, the role of B-1 cells in murine lupus still needs to be resolved. It is not known whether the aberrant trafficking of CXCL13-expressing DCs and the recruitment of B-1 cells into the thymus are involved directly in immune tolerance breakdown. A characteristic feature of murine lupus is the presence of high-affinity IgG autoantibodies for nuclear antigens. Therefore, it will be interesting to test for the hypothesis that tolerance breakdown might be associated with an affinity maturation of Ig genes in B-1 cells, resulting in the generation of plasma cells expressing pathogenic high-affinity autoantibodies.


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CHEMOKINE RECEPTORS AS MARKERS FOR T CELL SUBSETS
 
The lack of cell surface markers for the discrimination between memory and effector T cells used to be a major obstacle in the investigation of immunological memory. However, recent evidence suggests that distinct expression patterns of the chemokine receptors CCR7 and CXCR5 on CD4+ T cells allow a distinction between effector and memory T cell populations as reflected by different homing potentials and effector functions. T cell activation in the primary immune response results in the generation of specialized T cells including nonpolarized memory cells as well as polarized TH1 and TH2 effector cells. Nonpolarized T cells, i.e., cells secreting neither TH1 nor TH2 cytokines, persist as recirculating memory cells. Upon secondary challenge with antigen, these memory cells can give a rapid and enhanced response that also differs in quality. Recirculating nonpolarized T cells express high levels of CCR7 and L-selectin on the cell surface and were therefore termed central memory T (TCM) cells. In contrast, effector T cells producing cytokines such as IL-4 and interferon-{gamma} are CCR7- express only low levels of L-selectin and were therefore termed effector memory T (TEM) cells [50 ]. According to the expression levels of CCR7 and L-selectin, TCM cells home preferentially to secondary lymphoid organs, whereas TEM cells migrate preferentially into nonlymphoid tissues. Expression of the chemokine receptor CXCR5 allows a further division of the TCM cell pool into functionally different subpopulations: CXCR5+CCR7+ TCM cells are most likely precursors of follicular B helper T (TFH) cells, which are localized in secondary lymphoid tissues. Once immigrated into a secondary lymphoid organ, TFH precursor cells down-regulate CCR7, thereby enabling them to migrate into B cell follicles. CXCR5+CCR7- TFH cells lack TH1 or TH2 functions and phenotypes completely. Instead, they exert a classic Th function for B cells by stimulating the production of Igs [51 , 52 ]. A more recent study revealed that at least two subpopulations of TFH cells within secondary lymphoid organs need to be distinguished to precisely identify the cell subset with efficient B helper activity. Only CD57+ TFH cells that are located exclusively within GCs, but not CD57- TFH cells that are localized throughout primary follicles, interfollicular areas, and the T cell areas in secondary lymphoid tissues, are capable of efficiently stimulating B cell differentiation or Ig production [53 ].

Human TFH cells delivering B cell help represent a separate effector population apart from TH1 and TH2 cells. The latter are considered to be part of the CCR7-L-selectinlow TEM cell pool with peripheral tissue-homing capacity. In contrast, antibody production in mouse can be supported by adoptively transferred TH1 and TH2 cells in a CD154-dependent manner [54 ]. As TH2 cells localized more follicle-centered compared with TH1 cells in these experiments, it can be speculated that the different localization is a result of a differential expression of CCR7 on both cell populations. This hypothesis is supported by the observation that the transduction of TH2 cells with CCR7 redirects these cells into compartments typical for the homing of TH1 cells upon adoptive transfer [55 ]. The existence of a defined T helper cell population exerting B cell help has recently been confirmed in mice [56 ]. In this study, cell subsets were defined by patterns of adhesion molecules on the cell surface yet excluding chemokine receptors. Therefore, the B helper T cell subsets identified in the human and mouse system may not match exactly. Moreover, the expression pattern of CCR7 on effector T cells in mice may differ from the situation described for human CD4+ T cells.

A major issue to be resolved is the identification of the differentiation pathways leading from naïve to memory and effector T cells (Fig. 4 ). The ratio of effector and memory cells being produced during an immune response is affected by the duration and strength of the antigenic stimulation as well as by the type of DCs, cytokines, and costimulatory factors present in the secondary lymphoid tissue [57 58 59 ]. Following short-term stimulation, only a fraction of T cells produces effector-type T cell cytokines, whereas most cells remain nonpolarized [60 ]. These cells retain the ability to differentiate into TH1 and TH2 cells upon restimulation [61 ]. Therefore, the question arises as to whether naïve CD4+ T cells differentiate toward effector T cells along a linear pathway or to what extent the differentiation program of T cells allows for intraclonal diversification upon initial stimulation. This is interesting especially for TFH cells. Do they differentiate out of the TCM pool, independent of the well-described TH1 and TH2 effector cells? The presence of T cells expressing CCR7 and CXCR5 in combination with high levels of L-selectin in the peripheral blood, possible precursors of TFH cells (provisionally designated TCM1), favors this hypothesis. The precise role of the CCR7+CXCR5+ double-positive cells in the periphery still needs to be established. Recently, it was suggested that the expression of CXCR5 represents a transient phenomenon in the differentiation of all CD4+ T cells, thereby classifying these cells as pre-effector T cells [62 ]. Regarding peripheral CCR7+CXCR5+ cells, it is tempting to speculate that this cell pool also includes specialized populations of TH2 precursors or B-helper memory T cells (Fig. 4) .



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  		Figure 4. Hypothetical model for the differentiation of CD4+ Th cells into functionally distinct subpopulations. Antigenic stimulation of naïve T cells leads initially to the differentiation into nonpolarized TCM cells. Depending on the duration of the stimulus by DCs and cytokines, TCM cells may differentiate into polarized TEM cells of the TH1 or TH2 phenotype. Concomitantly, expression of CCR7 on the cell surface is down-regulated. Peripheral TCM1 cells expressing CXCR5 are most likely precursors of TFH cells in secondary lymphoid organs. Down-regulation of CCR7 upon entry into secondary lymphoid organs enables these cells to enter B cell follicles where they act as helper cells for B cells in the GC reaction. The high percentage of TFH cells expressing CD95 probably reflects their susceptibility to apoptosis [51 ]. TCM and TCM1 cells likely comprise functionally distinct subsets of T memory cells that have yet to be identified. Effector and central memory cells may have the capacity for self-renewal to maintain long-lasting memory. Patterns of cell-surface markers characteristic for the distinct T memory cell populations are indicated.

While trying to combine the novel classification of TCM and TEM cells with the classic TH1/TH2 model, the precise expression pattern of chemokine receptors on Th cells is still under debate [63 64 65 66 ]. Apart from differences in the experimental conditions being used for cell polarization, it must be considered that the polarization of CD4+ T cells in vitro differs from the conditions being effective in vivo. Moreover, TH1 and TH2 cells may represent rather broad categories, each comprising specialized subsets of Th cells with different phenotypes.

In summary, there are probably more intermediate stages of differentiation and more functionally distinct subsets of T cells hidden within the populations of TCM and TEM cells. For instance, CD4+CD45R0+CD25+ suppressor T cells need to be defined as a separate population in this concept. However, by merging the TH1/TH2 concept with the more recent model based on the dynamically regulated expression of chemokine receptors and adhesion molecules, we might better understand T cell function and differentiation in normal and pathogenic immune responses.

Received January 8, 2002; accepted March 7, 2002.


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