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Pioneering studies in the late 1960s demonstrated a fundamental role for T cells in providing help to B cells but the T cell subset responsible for this function remained widely unrecognized for more than four decades. After the turn of the millennium, accumulating evidence for the existence of what we now call T follicular helper (TFH) cells became too great to ignore.

In 1986, Timothy Mosmann and Robert Coffman introduced the concept that TH cells consist of two subsets (TH1 and TH2 cells) with distinct and cross-regulating cytokine profiles (Milestone 11). In their model, TH1 cells promote cell-mediated responses to intracellular pathogens, whereas TH2 cells promote humoral responses to extracellular pathogens. Neatly explaining the apparent polarized nature of various inflammatory diseases, this idea became so ingrained in scientific doctrine that any idea that challenged it faced strong opposition.

The notion of a third subset of TH cells emerged in 2000 with the identification of a specialized population of CXCR5+ T cells that localized to the B cell follicles. Producing few cytokines, these cells did not fit into the standard TH1–TH2 classification and instead were strong inducers of antibody production. Apparent effector functions and the follicular location of these cells led to the proposal of a new type of TH cell, termed ‘follicular B helper T cells’.

Following the identification of additional TH cell subsets — regulatory T cells (Milestone 15) and TH17 cells (Milestone 18) — the binomial TH1–TH2 classification was on shaky ground. Emerging evidence of the importance of stable contact-dependent T cell–B cell interactions in germinal centres for antibody reactions gave additional credence to the idea of a T cell subset that is responsible for this function.

The final tipping point came in 2009 when four research groups, led by Shane Crotty, Joe Craft, Chen Dong and Carola Vinuesa, simultaneously identified BCL-6 as a lineage-defining transcription factor in TFH cells. The four other known T cell subsets at that time already had their own unique master regulator that was central to the control of the differentiation and function of these cells. The identification of a TFH cell master regulator solidified the concept of a fifth T cell subset, linking BCL-6 function, TFH cell differentiation and T cell help to B cells in germinal centres.

Previous work in BCL-6-deficient mice had already shown an essential role for this transcription factor in antibody responses, but as germinal centre B cells also express BCL-6 this defect was attributed to a B cell-intrinsic effect. Gene expression profiling of the various T cell lineages revealed the selective expression of BCL-6 by TFH cells. A combination of techniques were used to assess the effects of loss or gain-of-function of BCL-6 in T cells, both in vitro and in mice, including the use of adoptive transfer experiments and mixed chimera approaches. These experiments demonstrated that T cell-specific expression of BCL-6 is both necessary and sufficient for TFH cell development and subsequent germinal centre reactions.

More specifically, microarray analysis revealed that BCL-6 promotes TFH cell differentiation by repression of transcription factors that are involved in the differentiation of other TH cell subsets (TH1 and TH17 cells). Johnston et al. further identified BLIMP1 as a reciprocal master repressor of TFH cell differentiation, by antagonising the effects of BCL-6 and functioning to prevent TFH cell gene expression in the other subsets.

The discovery of BCL-6 control of TFH cells and subsequent demonstration of the central role of TFH cells in B cell help ignited research in this area that continues to this day, including into the molecular and cellular mechanisms that regulate TFH cell differentiation and function, and the function of these cells in protective antibody responses during infection or vaccination as well as during pathogenic antibody responses in autoimmunity, cancer and allergy.

Further reading

Miller, J. F. & Mitchell, G.F. Cell to cell interaction in the immune response. I. Hemolysin-forming cells in neonatally thymectomized mice reconstituted with thymus or thoracic duct lymphocytes. J. Exp. Med. 128, 801–820 (1968).

Mitchell, G. F. & Miller, J. F. Cell to cell interaction in the immune response. II. The source of hemolysin-forming cells in irradiated mice given bone marrow and thymus or thoracic duct lymphocytes. J. Exp. Med. 128, 821–837 (1968).

Nossal, G. J. et al. Cell to cell interaction in the immune response. III. Chromosomal marker analysis of single antibody-forming cells in reconstituted, irradiated, or thymectomized mice. J. Exp. Med. 128, 839–853 (1968).

Mosmann, T. R. & Coffman, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–147 (1989).

Breitfeld, D. et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192, 1545–1552 (2000).

Schaerli, P. et al. CXC chemokine receptor 5 expression defined follicular homing T cells with B cell helper function. J. Exp. Med. 192, 1553–1562 (2000).

Kim, C. H. et al. Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. J. Exp. Med. 193, 1373–1381 (2001).

Qi, H. et al. SAP-controlled T–B cell interactions underlie germinal centre formation. Nature 455, 764–769 (2008).

Crotty, S. A brief history of T cell help to B cells. Nat. Rev. Immunol. 15, 185–189 (2015).