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 (T FH ), provides this help; however, the molecular requirements for T FH differentiation are unknown. We found that expression of the transcription factor Bcl6 in CD4 + T cells is both necessary and sufficient for in vivo T FH differentiation and T cell help to B cells in mice. In contrast, the transcription factor Blimp-1, an antagonist of Bcl6, inhibits T FH differentiation and help, thereby preventing B cell germinal center and antibody responses. These findings demonstrate that T FH cells are required for proper B cell responses in vivo and that Bcl6 and Blimp-1 play central but opposing roles in T FH differentiation.Each lineage of effector CD4 + T cells (T H 1, T H 2, T H 17, and T reg ) is defined and controlled by a unique master regulator transcription factor (T-bet, GATA3, RORγt, and Foxp3, respectively) (1). A proposed fifth effector subset, T follicular helper (T FH ) cells, is thought to provide help for the generation of B cell-mediated immune responses, including class switch recombination, germinal center differentiation, and affinity maturation (2). Here, we identified Bcl6 as a T FH master regulator and found that germinal center formation does not occur in the absence of T FH cells.

SUMMARY The nature of follicular helper CD4+ T (Tfh) cell differentiation remains controversial, including the minimal signals required for Tfh differentiation, and the time at which Tfh differentiation occurs. Here we determine that Tfh development initiates immediately during dendritic cell (DC) priming in vivo. We demonstrate that inducible costimulator (ICOS) provides a critical early signal to induce the transcription factor Bcl6, and Bcl6 then induces CXCR5, the canonical feature of Tfh cells. Strikingly, a bifurcation between Tfh and effector Th cells was measurable by the second cell division of CD4+ T cells, at day 2 after an acute viral infection: IL2Rαint cells expressed Bcl6 and CXCR5 (Tfh cell program), whereas IL2Rαhi cells exhibited strong Blimp1 expression that repressed Bcl6 (effector Th cell program). Virtually complete polarization between Bcl6+ Tfh cells and Blimp1+ effector Th cell populations developed by 72 hours, even without B cells. Tfh cells were subsequently lost in the absence of B cells, demonstrating a B cell requirement for maintenance of Bcl6 and Tfh cell commitment via sequential ICOS signals.

Tumors constitute highly suppressive microenvironments in which infiltrating T cells are "exhausted" by inhibitory receptors such as PD-1. Here we identify TIGIT as a coinhibitory receptor that critically limits antitumor and other CD8(+) T cell-dependent chronic immune responses. TIGIT is highly expressed on human and murine tumor-infiltrating T cells, and, in models of both cancer and chronic viral infection, antibody coblockade of TIGIT and PD-L1 synergistically and specifically enhanced CD8(+) T cell effector function, resulting in significant tumor and viral clearance, respectively. This effect was abrogated by blockade of TIGIT's complementary costimulatory receptor, CD226, whose dimerization is disrupted upon direct interaction with TIGIT in cis. These results define a key role for TIGIT in inhibiting chronic CD8(+) T cell-dependent responses.