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.