Follicular helper T cells as cognate regulators of B cell immunity

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Follicular helper T (TFH) cells are a class of helper T cells specialized in the cognate control of antigen-specific B cell immunity. Upon first contact with antigen-primed B cells, pregerminal center effector TFH cells promote B cell clonal expansion, antibody isotype switch, plasma cell differentiation, and the induction of germinal centers. By contrast, within germinal centers, TFH cells regulate the fate of antigen-specific GC B cells expressing high-affinity variant B cell receptors to promote memory B cell and long-lived plasma cell development. Recent studies unravel multiple signals controlling TFH development and functional subtypes of antigen-specific TFH cells, including memory TFH cells that accelerate memory B cell responses to antigen rechallenge in vivo.

Introduction

Helper T cell regulated B cell immunity is considered the basis of long-term immune protection provided by most vaccines in use today. There are spatial and temporal constraints on cognate programming events following antigen-specific priming that serve as developmental checkpoints in clonal selection and the commitment to adaptive immune function [1, 2]. The rules that govern information exchange at each developmental checkpoint define the molecular mechanisms of antigen-specific immune protection in this pathway and are the focus of the current review.

Follicular helper T (TFH) cells are now recognized as the class of helper T cells that regulate the multiple stages of B cell immunity (Figure 1) [3, 4, 5, 6]. After initial contact with antigen-experienced DC (Checkpoint I), antigen-specific effector TFH cells emerge as CXCR5+CCR7 TH cells that migrate to the follicular regions of lymphoid organs to form stable contacts with antigen-primed B cells (Checkpoint II). Subsequent to cognate B cell contact, a cohort of effector TFH cells migrate to germinal centers, form stable contacts with variant GC B cells (Checkpoint III) to regulate the development of antigen-specific memory B cell compartment in ways that remain poorly understood. Finally, memory TFH cells persist within the priming environment to regulate the antigen-specific memory B cell response to rechallenge (Checkpoint IV). We propose that the strength of antigen receptor binding, the duration of cellular contact and the molecular context of cognate interactions are the defining attributes of each developmental checkpoint in vivo.

Section snippets

Initiating adaptive immunity: Checkpoint I

Vaccines provide foreign antigen within an inflammatory context to initiate dendritic cell (DC) maturation. Antigen-experienced DC will express peptide–MHC class II (pMHCII) complexes and a spectrum of secreted and surface-expressed molecules to recruit naive pMHCII-specific TH cells (Checkpoint Ia), promote TH clonal expansion and effector TH cell differentiation. The strength of TCR–pMHCII interactions and the extended molecular context of these cognate events impact antigen-specific TH cell

Pre-GC effector TFH cells: Checkpoint II

The cardinal feature of antigen-specific CXCR5+ TFH cells is migration toward the B cell zones of secondary lymphoid tissue [12, 13], and then, placement of an ongoing immune response within the GCs [14, 15]. Functional analysis in vitro [15], and then, in vivo upon adoptive transfer [16] established the propensity of the CXCR5+ TH compartment to support antibody production by B cells. The presence of antigen-specific TH cells within the GC has been described in human tonsils [17, 18] and

Effector TFH function: lineage and location

The spectrum of helper T cell functions with regulatory impact on different cellular targets is extensive and expanding [29]. The programming and organization of these functions across different subtypes of effector TH cells is still an area of intense research. In this context, the assignment of cytokine production by effector TFH cell functions remains controversial. Early assessments of cytokine production by in vitro restimulated CXCR5+ TFH cells indicated IL-2, IFN-γ, and IL-10 from human

Germinal centers: Checkpoint III

The GC cycle of activity begins with recruitment and massive expansion of antigen-specific B cells in the B cell zones of secondary lymphoid tissue. There is evidence for BCR-affinity-based selection for entry into the GC cycle [43]. It is curious to speculate that the strength of pMHCII–TCR contact at Checkpoint II influences this developmental progression. In this model, the initial strength of BCR binding to antigen may be indirectly responsible for the duration of effector TFH cell pMHCII+

GC TFH function: separate B cell lineages

In their recent analysis of TFH–GC B cell doublets, Locksey and colleagues [40••] provided another surprising and potentially important insight into our understanding of GC–cognate interactions. These studies isolated doublets from day 21 of an immune response and demonstrated the phenotype of TFH cells and phenotype/genotype of antigen-specific GC B cells. Most remarkably, IL-4 producing TFH cells paired with IgG1 expressing GC B cells and IFN-γ producing TFH cells paired with IgG2a expressing

Memory B cell response: Checkpoint IV

CXCR5+ TH cells were first reported in the peripheral blood of humans [56] but were subsequently demonstrated to express reduced capacity to promote antibody production in vitro [31]. How these circulating CXCR5+ cells relate to the resident TFH compartment in peripheral LNs [4, 30•] has not been resolved. Our recent demonstration of a memory counterpart to the antigen-specific effector TFH population indicates a cohort of CXCR5+ TFH cells that persists locally to regulate accelerated memory B

Conclusions

TFH cells define a class of regulatory TH cells specialized for the cognate control of all stages of antigen-specific B cell development. Recent advances in this field indicate that initial contact with pMHCII-expressing DC induces multiple subtypes of CXCR5+ effector TFH cells producing different cytokines involved in the programming of B cell immunity. Antibody isotype switch is one major facet of the B cell response regulated by cognate control that may define antigen-specific B lineage

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (57)

  • C.G. Vinuesa et al.

    Follicular B helper T cells in antibody responses and autoimmunity

    Nat Rev Immunol

    (2005)
  • N. Fazilleau et al.

    The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding

    Nat Immunol

    (2009)
  • A.L. Gavin et al.

    Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling

    Science

    (2006)
  • C. Pasare et al.

    Control of B-cell responses by Toll-like receptors

    Nature

    (2005)
  • F.D. Batista et al.

    The who, how and where of antigen presentation to B cells

    Nat Rev Immunol

    (2009)
  • K.M. Ansel et al.

    In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines

    J Exp Med

    (1999)
  • L.S. Walker et al.

    Compromised OX40 function in CD28-deficient mice is linked with failure to develop CXC chemokine receptor 5-positive CD4 cells and germinal centers

    J Exp Med

    (1999)
  • D. Breitfeld et al.

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

    J Exp Med

    (2000)
  • P. Schaerli et al.

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

    J Exp Med

    (2000)
  • D.J. Campbell et al.

    Separable effector T cell populations specialized for B cell help or tissue inflammation

    Nat Immunol

    (2001)
  • K.A. Fuller et al.

    T cells within germinal centers are specific for the immunizing antigen

    J Immunol

    (1993)
  • M.B. Bowen et al.

    Germinal center T cells are distinct helper-inducer T cells

    Hum Immunol

    (1991)
  • P. Garside et al.

    Visualization of specific B and T lymphocyte interactions in the lymph node

    Science

    (1998)
  • L.J. McHeyzer-Williams et al.

    Evolution of antigen-specific T cell receptors in vivo: preimmune and antigen-driven selection of preferred complementarity-determining region 3 (CDR3) motifs

    J Exp Med

    (1999)
  • B. Zheng et al.

    T helper cells in murine germinal centers are antigen-specific emigrants that downregulate Thy-1

    J Exp Med

    (1996)
  • I.C. MacLennan

    Germinal centers

    Annu Rev Immunol

    (1994)
  • T. Okada et al.

    Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells

    PLoS Biol

    (2005)
  • P.L. Schwartzberg et al.

    SLAM receptors and SAP influence lymphocyte interactions, development and function

    Nat Rev Immunol

    (2009)
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