STAT5 is a negative regulator of Bcl6-mediated TFH differentiation (63.2)

Abstract

Abstract Follicular helper T cells (TFH) constitute the CD4+ T cell effector subset that is specialized to provide germinal center B cell help. TFH differentiation is driven by the transcription factor Bcl6, and recent studies have identified cytokine and cell-cell signals that are required for optimal expression of Bcl6. However, the mechanisms underlying the negative regulation of TFH differentiation have been less clear. Here, we show that STAT5 was a key inhibitor of TFH differentiation and function. Constitutive STAT5 signaling in activated CD4+ T cells selectively blocked TFH differentiation, resulting in a collapse of the germinal center reaction. Conversely, STAT5-deficient CD4+ T cells (mature STAT5flox/flox CD4+ T cells transduced with a Cre-expressing retrovirus) rapidly upregulated Bcl6 expression and preferentially differentiated into TFH cells. STAT5 signaling failed to inhibit TFH differentiation in the absence of the transcription factor Blimp-1. We have previously shown that Blimp-1 is a direct repressor of Bcl6-mediated TFH differentiation (Science, 2009). These results demonstrate that STAT5 and Blimp-1 collaborate to negatively regulate TFH differentiation.