STAT5 is a potent negative regulator of TFH cell differentiation.

Follicular helper T cells (T(FH) cells) constitute the CD4(+) T cell subset that is specialized to provide help to germinal center (GC) B cells and, consequently, mediate the development of long-lived humoral immunity. T(FH) cell differentiation is driven by the transcription factor Bcl6, and recent studies have identified cytokine and cell-cell signals that drive Bcl6 expression. However, although T(FH) dysregulation is associated with several major autoimmune diseases, the mechanisms underlying the negative regulation of T(FH) cell differentiation are poorly understood. In this study, we show that STAT5 inhibits T(FH) cell differentiation and function. Constitutive STAT5 signaling in activated CD4(+) T cells selectively blocked T(FH) cell differentiation and GCs, and IL-2 signaling was a primary inducer of this pathway. Conversely, STAT5-deficient CD4(+) T cells (mature STAT5(fl/fl) CD4(+) T cells transduced with a Cre-expressing vector) rapidly up-regulated Bcl6 expression and preferentially differentiated into T(FH) cells during T cell priming in vivo. STAT5 signaling failed to inhibit T(FH) cell differentiation in the absence of the transcription factor Blimp-1, a direct repressor of Bcl6 expression and T(FH) cell differentiation. These results demonstrate that IL-2, STAT5, and Blimp-1 collaborate to negatively regulate T(FH) cell differentiation.