The elusive identity of T follicular helper cells

doi:10.1016/j.it.2010.07.001

Trends in Immunology

Volume 31, Issue 10, October 2010, Pages 377-383

https://doi.org/10.1016/j.it.2010.07.001 Get rights and content

Follicular helper T (Tfh) cells provide help to B cells and allow formation of long-lived antibody responses. Despite an improved understanding of the molecular program that drives Tfh cell formation, their definition remains elusive: neither follicular homing ability, Bcl-6 expression nor IL-21 secretion are exclusive properties of T cells that help B cells, and not all follicular T cells are B cell helpers. Indeed some follicular T cells appear to be suppressive. Furthermore, Tfh cells evolve during an immune response and B cells that have recently bound antigen, germinal center (GC) B cells and plasmablasts interact with phenotypically distinct Tfh cells. Here we propose that distinction between non-GC Tfh and GC Tfh cells might reconcile emerging controversies on Tfh cytokine secretion and the requirement of T–B cell interactions and SAP expression for Tfh formation.

Section snippets

Follicular helper T (Tfh) cells: the challenge of a definition

Within secondary lymphoid organs, Tfh cells provide help to B cells to allow formation of long-lived antibody responses. Beyond their ability to provide B cell help, Tfh cells are arguably the helper T (Th) cell subset that has been most challenging to define. This is partly because: (i) T cell–B cell interactions occur at several distinct phases of thymus-dependent (TD) antibody responses and T cells evolve in phenotype and function during this response; (ii) CD4 T cells in B cell follicles

Defining Tfh cells: the controversies and dilemmas

As highlighted in Figure 1 and reviewed in [3], during immune responses to TD protein antigens, primed T cells initially interact and provide help to B cells at the T–B border, and at this stage immunoglobulin isotype switching is initiated 4, 5, 6. B cells then begin to divide at the perimeter of the follicle 7, 8. Some B blasts migrate to extrafollicular sites and differentiate into low-affinity (unmutated) plasmablasts that may contact and possibly receive help from rare T cells at these

The evolving phenotype of Tfh cells

Until recently, it has been difficult to distinguish the different types of Tfh cells on the basis of surface phenotype. Nevertheless, combined evidence from several groups suggests that GC Tfh cells are phenotypically distinct from Tfh cells at other locations or developmental stages.

Concluding remarks

Tfh cells have emerged as a subset of Th cells with a unique transcriptional profile and functional capabilities. As we have begun to understand Tfh development, numerous controversies have arisen as a result of the described discrepancies in phenotype, cytokine secretion pattern, and the requirement for interaction with different APCs for Tfh formation. Here, we have reviewed evidence that suggests that Tfh cells that interact with GC B cells – GC Tfh cells – are different in phenotype and

Acknowledgements

C.G.V. is supported by a Viertel Senior Medical Research Fellowship and NHMRC project and program grants. D.Y. is supported by a Cancer Institute New South Wales Fellowship, an NHMRC Fellowships and an NHMRC program grant to Charles R Mackay.

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Previous research has recently indicated that TLR7 is able to induce CD4⁺T cell anergy, which is the opposite of the role it plays in innate immune cells. Therefore, TLR7 ligands may be used as a manner in which to induce CD4⁺T cells “tolerance” in autoimmune diseases. T follicular helper (Tfh) cells were demonstrated to be a subset of CD4⁺T cells that help B cells produce antibodies. The abnormal activity of Tfh cells, though, is their function as a primary pathogenic factor in systemic lupus erythematosus (SLE). However, the role of TLR7 in Tfh cells is not clear. Our study was aimed at determining the influence of TLR7 on Tfh cells in a murine model of SLE (MRL/lpr mice). We were surprised to find that the frequency of Tfh cells and germinal center (GC) B cells was significantly reduced after treatment with the TLR7 agonist imiquimod. Imiquimod also significantly reduced the expression of inducible costimulatory molecule (ICOS) and programmed death 1(PD-1) in Tfh cells and decreased IL-21 secretion. Moreover, imiquimod significantly reduced the mRNA expression of several transcription factors, including Bcl-6, c-Maf, Batf3, Nfatc2 and Stat3, and enhanced the expression of Prdm1 and Stat5b in CD4⁺T cells. Imiquimod also ameliorated the progression of SLE in MRL/lpr mice by inhibiting anti-dsDNA antibodies and antinuclear antibody (ANA) secretion in the serum. Our findings indicated that TLR7 inhibited the development of Tfh cells both in vivo and ex vivo, which depended on many transcription factors aside from Bcl-6. Our results demonstrated that a TLR7 agonist has the potential to be used to inhibit Tfh cell responses during SLE.
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Trends in Immunology

ReviewThe elusive identity of T follicular helper cells

Section snippets

Follicular helper T (Tfh) cells: the challenge of a definition

Defining Tfh cells: the controversies and dilemmas

The evolving phenotype of Tfh cells

Concluding remarks

Acknowledgements

Curr. Opin. Immunol.

Immunity

Immunity

Immunity

Blood

Immunity

Semin. Immunol.

Immunity

Immunity

Immunity

Immunity

Immunity

Follicular B helper T cells in antibody responses and autoimmunity

Nat. Rev. Immunol.

In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. I. The architecture and dynamics of responding cell populations

J. Exp. Med.

T helper 1 (Th1) and Th2 characteristics start to develop during T cell priming and are associated with an immediate ability to induce immunoglobulin class switching

J. Exp. Med.

Visualization of the genesis and fate of isotype-switched B cells during a primary immune response

J. Exp. Med.

Antigen affinity controls rapid T-dependent antibody production by driving the expansion rather than the differentiation or extrafollicular migration of early plasmablasts

J. Immunol.

ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity

J. Exp. Med.

Persistence of memory B cells in mice deprived of T cell help

Int. Immunol.

Naive T-cell receptor transgenic T cells help memory B cells produce antibody

Immunology

Two waves of memory B-cell generation in the primary immune response

Int. Immunol.

IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses

J. Exp. Med.

IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism

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.

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

J. Exp. Med.

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

J. Exp. Med.

Population analysis of CD4+ T cell chemokine receptor transcript expression during in vivo type-1 (mycobacterial) and type-2 (schistosomal) immune responses

J. Leukoc. Biol.

Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation

J. Immunol.

The germinal center response is impaired in the absence of T cell-expressed CXCR5

Eur. J. Immunol.

T cell accumulation in B cell follicles is regulated by dendritic cells and is independent of B cell activation

J. Exp. Med.

Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation

Science

SAP-controlled T-B cell interactions underlie germinal centre formation

Nature

Follicular helper T cells are required for systemic autoimmunity

J. Exp. Med.

Review
The elusive identity of T follicular helper cells