Bcl6 and Blimp-1 regulate the differentiation of Follicular Helper T cells

CD4⁺ T cells are potent regulators of adaptive immune responses. It is well known that there are at least four independent CD4⁺ T cell effector subsets: TH1, TH2, TH17, and Treg. One critical function of CD4⁺ T cells is to provide B cell help; however, it has been unclear if this help is provided by all CD4⁺ T cells, by TH2 cells, or by a fifth subset of effector cells. Because each effector subset is controlled by a master regulator (T-bet, GATA3, ROR[gamma]t, and Foxp3 respectively), we hypothesized that if the CD4⁺ T cells that provide B cell help constitute a distinct effector subset, they too would possess a master regulator. Here, we show that the transcription factor Bcl6 is the master regulator of a subset of effector CD4⁺ T cells that is specialized to provide B cell help: the Follicular Helper T cells (TFH). CD4⁺ T cells constitutively expressing Bcl6 differentiated fully to TFH in vivo and provided B cell help, resulting in increased germinal centers and enhanced antibody responses. Furthermore, CD4⁺ T cells deficient in Bcl6 failed to differentiate into TFH cells, and were unable to sustain the germinal center reaction. Multiple Bcl6 repression domains were required for optimal TFH differentiation. Expression of Bcl6 was dependent on interaction with antigen-presenting cells, such as cognate B cells. Surprisingly, STAT3 signaling, which has been proposed to induce Bcl6 expression, was neither necessary nor sufficient to drive TFH differentiation. Negative regulation is also a critical component of most biological processes. Bcl6 and the transcription factor Blimp-1 are mutual antagonists, and we found that Blimp-1 was highly downregulated in TFH cells. Forced expression of Blimp-1 blocked TFH differentiation and help to B cells, but did not impair non-TFH effector cell differentiation. STAT5 signaling collaborated with Blimp-1 in vivo to inhibit TFH differentiation. Consequently, effector CD4⁺ T cells lacking either Blimp-1 or STAT5 preferentially differentiated into TFH cells in vivo. These findings demonstrate that TFH cells constitute a critically important and distinct CD4⁺ T cell effector subset, and that Bcl6 and Blimp-1 play central but opposing roles in TFH differentiatio