Amanda C. Poholek

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

T Follicular Helper Cell Differentiation When B cells respond to an infection, they often require help from CD4+ T cells to mount a proper response. It is thought that a subset of CD4+ effector T cells, called T follicular helper cells (TFH), performs this function. Several subsets of effector CD4+ T cells arise, depending on the type of infection, which have distinct transcriptional programs driving their differentiation. Whether this is also the case for TFH cells has not been clear (see the Perspective by Awasthi and Kuchroo). Nurieva et al. (p. 1001, published online 23 July) and Johnston et al. (p. 1006; published online 16 July) now demonstrate that the transcription factor Bcl6 is both necessary and sufficient for TFH differentiation and subsequent B cell–mediated immunity, suggesting that it is a master regulator of this lineage. Johnston et al. also show that expression of Bcl6 and the transcription factor, Blimp-1, are reciprocally regulated in TFH cells and that, when ectopically expressed, Blimp-1 inhibits TFH development. The transcription factors that regulate follicular T helper cell differentiation are identified. Effective B cell–mediated immunity and antibody responses often require help from CD4+ T cells. It is thought that a distinct CD4+ effector T cell subset, called T follicular helper cells (TFH), provides this help; however, the molecular requirements for TFH differentiation are unknown. We found that expression of the transcription factor Bcl6 in CD4+ T cells is both necessary and sufficient for in vivo TFH differentiation and T cell help to B cells in mice. In contrast, the transcription factor Blimp-1, an antagonist of Bcl6, inhibits TFH differentiation and help, thereby preventing B cell germinal center and antibody responses. These findings demonstrate that TFH cells are required for proper B cell responses in vivo and that Bcl6 and Blimp-1 play central but opposing roles in TFH differentiation.

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

The role of specialized follicular helper T (TFH) cells in the germinal center has become well recognized, but it is less clear how effector T cells govern the extrafollicular response, the dominant pathway of high-affinity, isotype-switched autoantibody production in the MRL/MpJ-Faslpr (MRLlpr) mouse model of lupus. MRLlpr mice lacking the Icos gene have impaired extrafollicular differentiation of immunoglobulin (Ig) G+ plasma cells accompanied by defects in CXC chemokine receptor (CXCR) 4 expression, interleukin (IL) 21 secretion, and B cell helper function in CD4 T cells. These phenotypes reflect the selective loss of a population of T cells marked by down-regulation of P-selectin glycoprotein ligand 1 (PSGL-1; also known as CD162). PSGL-1lo T cells from MRLlpr mice express CXCR4, localize to extrafollicular sites, and uniquely mediate IgG production through IL-21 and CD40L. In other autoimmune strains, PSGL-1lo T cells are also abundant but may exhibit either a follicular or extrafollicular phenotype. Our findings define an anatomically distinct extrafollicular population of cells that regulates plasma cell differentiation in chronic autoimmunity, indicating that specialized humoral effector T cells akin to TFH cells can occur outside the follicle.

In vivo regulation of Bcl6 and T follicular helper cell development

Follicular helper T (TFH) cells, defined by expression of the surface markers CXCR5 and programmed death receptor-1 (PD-1) and synthesis of IL-21, require upregulation of the transcriptional repressor Bcl6 for their development and function in B cell maturation in germinal centers. We have explored the role of B cells and the cytokines IL-6 and IL-21 in the in vivo regulation of Bcl6 expression and TFH cell development. We found that TFH cells are characterized by a Bcl6-dependent downregulation of P-selectin glycoprotein ligand 1 (PSGL1, a CCL19- and CCL21-binding protein), indicating that, like CXCR5 and PD-1 upregulation, modulation of PSGL1 expression is part of the TFH cell program of differentiation. B cells were neither required for initial upregulation of Bcl6 nor PSGL1 downregulation, suggesting these events preceded T–B cell interactions, although they were required for full development of the TFH cell phenotype, including CXCR5 and PD-1 upregulation, and IL-21 synthesis. Bcl6 upregulation and TFH cell differentiation were independent of IL-6 and IL-21, revealing that either cytokine is not absolutely required for development of Bcl6+ TFH cells in vivo. These data increase our understanding of Bcl6 regulation in TFH cells and their differentiation in vivo and identifies a new surface marker that may be functionally relevant in this subset.

Thymic self-reactivity selects natural interleukin 17-producing T cells that can regulate peripheral inflammation

Interleukin 17 (IL-17)-producing CD4+ helper T cells (TH-17 cells) share a developmental relationship with Foxp3+ regulatory T cells (Treg cells). Here we show that a TH-17 population differentiates in the thymus in a manner influenced by recognition of self antigen and by the cytokines IL-6 and transforming growth factor-β (TGF-β). Like previously described TH-17 cells, the TH-17 cells that developed in the thymus expressed the transcription factor RORγt and the IL-23 receptor. These cells also expressed α4β1 integrins and the chemokine receptor CCR6 and were recruited to the lung, gut and liver. In the liver, these cells secreted IL-22 in response to self antigen and mediated host protection during inflammation. Thus, TH-17 cells, like Treg cells, can be selected by self antigens in the thymus.

B cells in T follicular helper cell development and function: separable roles in delivery of ICOS ligand and antigen.

B cells are required for follicular Th (Tfh) cell development, as is the ICOS ligand (ICOS-L); however, the separable contributions of Ag and ICOS-L delivery by cognate B cells to Tfh cell development and function are unknown. We find that Tfh cell and germinal center differentiation are dependent on cognate B cell display of ICOS-L, but only when Ag presentation by the latter is limiting, with the requirement for B cell expression of ICOS-L overcome by robust Ag delivery. These findings demonstrate that Ag-specific B cells provide different, yet compensatory, signals for Tfh cell differentiation, while reconciling conflicting data indicating a requirement for ICOS-L expression on cognate B cells for Tfh cell development with those demonstrating that the latter requirement could be bypassed in lieu of that tendered by noncognate B cells. Our findings clarify the separable roles of delivery of Ag and ICOS-L by cognate B cells for Tfh cell maturation and function, and have implications for using therapeutic ICOS blockade in settings of abundantly available Ag, such as in systemic autoimmunity.

Competing for help: new insights into the function of follicular helper T cells

The development and function of the CD4 T-cell subset that controls B-cell responses to protein antigens has lagged behind our knowledge of other effector lineages of CD4 T cells. Two new studies published in Nature Immunology1, 2 shed light on the requirements for CD4 T cells that are selected for B cell help, and how they mediate that function through the secretion of cytokines.