CXCR5+ T cells: follicular homing takes center stage in T-helper-cell responses

doi:10.1016/S1471-4906(02)02218-4

Trends in Immunology

Volume 23, Issue 5, 1 May 2002, Pages 250-254

https://doi.org/10.1016/S1471-4906(02)02218-4 Get rights and content

Abstract

The development of effector and memory T cells is a multistep and spatially controlled process. Resting T helper (Th) cells are primed during antigen-specific contact with dendritic cells in the T-cell zone of secondary lymphoid tissues and then, develop further to become specialized effector or memory T cells. Chemokines are key players in the control of cellular traffic. Here, we argue for a crucial role for the chemokine B-cell-attracting chemokine 1 (BCA-1/CXCL13) and its receptor CXC-chemokine receptor 5 (CXCR5) in the follicular homing and further differentiation of newly primed, nonpolarized Th cells. The rapid induction of this follicular localization program in these cells supports the concept of an unprecedented role for the B-cell compartment in Th-cell responses.

Section snippets

CXCR5 identifies follicular-homing T helper cells

CXCR5 is expressed on a subset of peripheral-blood and tonsillar memory CD4⁺ T cells, but is absent from naive CD4⁺ T cells, and T helper 1 (Th1) and Th2 cells (Table 1) 12., 13., 14., 15.. In addition, CXCR5 is present on a minor subset (<2%) of blood memory CD8⁺ T cells. In the tonsils, CXCR5⁺ T cells are highly enriched (>95% of CD4⁺CD45RO⁺ T cells) and express activation markers, but lack the capacity to participate in inflammatory responses, as indicated by the absence of receptors for

Rapid induction of CXCR5 during Th-cell activation

CXCR5 is expressed rapidly on T cells during primary immune responses in mice, and the follicular localization of these T cells was shown to depend on adjuvant 25., 26.. This is in agreement with previous reports describing the one-way traffic of newly activated CD4⁺ T cells into B-cell follicles 27., 28., 29., 30., 31.. Notably, OX40 (CD134) signaling was shown to be linked with the expression of CXCR5 by T cells and T-cell relocation into follicles [32]. The in vitro induction of CXCR5

T_FH cells at the gateway of effector Th-cell generation

The early acquisition of expression of CXCR5 during Th-cell activation indicates that the follicular-homing capability of T_FH cells is linked intimately with the priming process, which precedes cellular differentiation into bona fide effector cells. It follows that all types of effector Th cell, including Th1 and Th2 cells, which are programmed to enter inflammatory sites in the periphery (Table 1), as well as B-helper T cells, which control germinal-center reactions in the B-cell zone, are

Concluding remarks

This discussion is based primarily on our knowledge of chemokine-mediated lymphocyte traffic. For that reason, we propose an enforced, rather than diffusion-driven, relocation of T_FH cells, which are Ag-primed but not yet polarized, from the site of initial Ag contact in the T-cell zone to the B-cell compartment. Our speculation about the further development of T_FH cells within follicles involves ICOSL⁺ B cells (ICOSL expression on CXCR5⁺ DCs has yet to be shown) as alternative APCs for

Acknowledgements

This work was supported by grant 31-055996.98 from the Swiss National Science Foundation and grant 99.0471-5 from the Bundesamt für Bildung und Wissenschaft.

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CXCL13, also known as B cell-attracting chemokine-1 (BCA-1) or B-lymphocyte chemoattractant (BLC), is mainly expressed within follicles of secondary lymphoid tissues which include stromal cells in B-cell follicles, dendritic cells, and T follicular helper cells [13,14]. When binds to its exclusive receptor CXCR5, CXCL13 can regulate homing of B cells and subsets of T cells to lymphoid follicles [15,16]. Earlier reports have demonstrated that CXCL13 was implicated in the formation of lymphoid tissue in chronic inflammation such as multiple sclerosis, rheumatoid arthritis or neuroinflammation [17–19].
Clostridium difficile infection (CDI) is the leading cause of antibiotic- and healthcare-associated diarrhea. CXCL13 is a well-known CXC chemokine involved in inflammation, but its role in CDI remains unknown. In this study, serum and fecal samplings were collected from 51 CDI patients, 50 diarrhea patients without CDI and 50 healthy control subjects to determine the CXCL13 levels by enzyme-linked immunosorbent assay (ELISA). Besides, a mouse model of C. difficile infection was established, and murine serum and colon tissues were collected for detection of CXCL13 expression using quantitative real-time RT-PCR, ELISA, Western blot, or immunohistochemistry. We found that CXCL13 concentration in serum and fecal samples from CDI patients was significantly higher compared with that from diarrhea patients without CDI and that from healthy controls. Elevated serum CXCL13 positively and significantly correlated with blood markers of inflammation and yielded an increased area under the ROC curve of 0.929. In murine C. difficile infection, CXCL13 were also dramatically increased in serum and infected colon tissues at the transcriptional and protein levels. The elevated CXCL13 levels positively and significantly correlated with inflammatory scores. Therefore, CDI is associated with enhanced release of CXCL13. This study indicated that CXCL13 may be pathogenically involved in CDI and served as a potential new biomarker for diagnosis and prognosis in CDI.
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A central effort in HIV vaccine development is to generate protective broadly neutralizing antibodies, a process dependent on T follicular helper (Tfh) cells. The feasibility of using peripheral blood counterparts of lymph node Tfh cells to assess the immune response and the influence of viral and vaccine antigens on their helper functions remain obscure. We assessed circulating HIV-specific IL-21⁺CD4⁺ T cells and showed transcriptional and phenotypic similarities to lymphoid Tfh cells, and hence representing peripheral Tfh (pTfh) cells. pTfh cells were functionally active and B cell helper quality differed depending on antigen specificity. Furthermore, we found higher frequency of pTfh cells in peripheral blood mononuclear cell specimens from the ALVAC+AIDSVAX (RV144) HIV vaccine trial associated with protective antibody responses compared to the non-protective DNA+Ad5 vaccine trial. Together, we identify IL-21⁺CD4⁺ T cells as pTfh cells, implicating them as key populations in the generation of vaccine-evoked antibody responses.
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Nasopharynx-associated lymphoid tissue (NALT), constituting mainly Waldeyer's ring in humans, is a unique inductive site for T- and B-cell responses with abundant plasma cell generation. The most prominent NALT structures are the unpaired nasopharyngeal tonsil (adenoids) and the paired palatine tonsils, which appear functionally similar to the paired rodent NALT structures located dorsal to the cartilaginous soft palate. All human NALT structures show similarities with lymph nodes and participate in both systemic-type and mucosal secretory-type immunity. Primary follicles occur at 16 weeks of gestation, which is comparable to Peyer's patches but different from rodent NALT whose organogenesis begins at birth. Germinal centers arise shortly after birth in T-cell-dependent B-cell responses and are associated with somatic hypermutation of immunoglobulin (Ig) V-region. Downstream switching to various Ig isotypes also takes place, with or without concurrent expression of the J-chain gene. The J chain is a crucial part of dimeric IgA and pentameric IgM, making these Ig polymers able to interact with the epithelial polymeric Ig receptor. This interaction is central in the formation of secretory IgA and secretory IgM. Accumulating evidence suggests a major role for NALT in antibody-mediated immunity of the airways and associated glands.
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Intestinal plasma cells are largely derived from B cells initially activated in gut-associated lymphoid tissue (GALT), although in mice the peritoneal cavity also contributes. Insufficient knowledge exists about the uptake, processing, and presentation of antigens to accomplish priming and sustained expansion of mucosal B cells. Also, it is unclear why the germinal center reaction in GALT so strikingly promotes class switch to IgA and expression of the J chain, although the commensal microbiota appears crucial for B cell diversification and memory. Migration of activated B cells from GALT to the intestinal lamina propria is guided by well-defined adhesion molecules and chemokines/chemokine receptors, but the cues directing the homing of mucosal B cells to secretory effector sites beyond the gut require better definition. In this respect, the role of Waldeyer's ring (including the adenoids and palatine tonsils) as nasopharynx-associated lymphoid tissue (NALT) in humans must be better defined, although the balance of evidence suggests that it functions like the characteristic NALT structures in rodents. Altogether, data suggest a remarkable compartmentalization of the mucosal B cell system that must be considered in the development of effective vaccines to protect specifically the airways and the gut.
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A subset of CD4+ T helper cells termed follicular B-helper T (Tfh) cells have been observed in the GC which displays potent assistance for antibody responses (Fazilleau et al., 2009a; McHeyzer-Williams et al., 2009; Kerfoot et al., 2011). Tfh cells retain intense expression of CXCR5, which directs these cells toward CXCL13-rich areas within the GC (Schaerli et al., 2000; Moser et al., 2002). Tfh cells express a number of costimulatory molecules, such as ICOS and CD40L that have the capacity to restrain their interaction with B cells and APCs, including CTLA-4 and PD-1, which may reflect their discriminating role in the GC (Rasheed et al., 2006; Akiba et al., 2005).
Lycium barbarum polysaccharides (LBP) have been shown to play a variety of immune-modulatory functions which include activation of T and B cells. Follicular helper T (Tfh) cells are now recognized as a subset of helper T cells which regulate the multiple stages of B cell maturation and function. In our current study, we found that LBP were able to activate CXCR5+PD-1+ Tfh cells and induce IL-21 secretion. At the same time LBP also promoted the formation of germinal centers (GC) and production of GL-7+B220+GC B cells. LBP as an adjuvant could increase generation of rAd5VP1-induced Tfh cells. Our results indicate that LBP might enhance T cell-dependent Ab responses by acting as an adjuvant for the generation of Tfh cells. Future vaccine designs might therefore be targeted to induce strong antigen-specific Tfh responses in order to boost its protective effects.
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Trends in Immunology

OpinionCXCR5+ T cells: follicular homing takes center stage in T-helper-cell responses

Abstract

Section snippets

CXCR5 identifies follicular-homing T helper cells

Rapid induction of CXCR5 during Th-cell activation

TFH cells at the gateway of effector Th-cell generation

Concluding remarks

Acknowledgements

Cell

Blood

Trends Immunol.

Immunity

Immunity

Immunol. Today

Curr. Opin. Immunol.

Cell

Curr. Opin. Immunol.

Adv. Immunol.

The role of chemokine receptors in primary, effector and memory immune responses

Annu. Rev. Immunol.

Lymphocyte traffic control by chemokines

Nat. Immunol.

Lymphocyte homing and homeostasis

Science

Two subsets of memory T lymphocytes with distinct homing potentials and effector functions

Nature

Distinct migration patterns of naive and effector CD8 T cells in the spleen: correlation with CCR7 receptor expression and chemokine reactivity

Eur. J. Immunol.

CCR7 expression and memory T-cell diversity in humans

J. Immunol.

Rules of chemokine receptor association with T-cell polarization in vivo

J. Clin. Invest.

A chemokine-driven positive-feedback loop organizes lymphoid follicles

Nature

CXCR5-deficient mice develop functional germinal centers in the splenic T-cell zone

Eur. J. Immunol.

A coordinated change in chemokine responsiveness guides plasma-cell movements

J. Exp. Med.

CXC-chemokine receptor 5 expression defines follicular homing T cells with B-cell helper function

J. Exp. Med.

Follicular B-helper T cells express CXC-chemokine receptor 5, localize to B-cell follicles and support immunoglobulin production

J. Exp. Med.

Opinion
CXCR5⁺ T cells: follicular homing takes center stage in T-helper-cell responses

T_FH cells at the gateway of effector Th-cell generation