An Inhibitory Role for the Transcription Factor Stat3 in Controlling IL-4 and Bcl6 Expression in Follicular Helper T Cells

摘要

The transcription factor Bcl6 is required for development of follicular helper T (T-FH) cells. Cytokines that activate Stat3 promote Bcl6 expression and T-FH cell differentiation. Previous studies with an acute virus infection model showed that T-FH cell differentiation was decreased but not blocked in the absence of Stat3. In this study, we further analyzed the role of Stat3 in T-FH cells. In Peyer's patches, we found that compared with wild-type, Stat3-deficient T-FH cells developed at a 25% lower rate and expressed increased IFN-gamma and IL-4. Whereas Peyer's patch germinal center B cells developed at normal numbers with Stat3-deficient T-FH cells, IgG1 class switching was greatly increased. Following immunization with sheep RBCs, splenic Stat3-deficient T-FH cells developed at a slower rate than in control mice, and splenic germinal center B cells were markedly decreased. Stat3-deficient T-FH cells developed poorly in a competitive bone marrow chimera environment. Under all conditions tested, Stat3-deficient T-FH cells overexpressed both IL-4 and Bcl6, a pattern specific for the T-FH cell population. Finally, we found in vitro that repression of IL-4 expression in CD4 T cells by Bcl6 required Stat3 function. Our data indicate that Stat3 can repress the expression of Bcl6 and IL-4 in T-FH cells, and that Stat3 regulates the ability of Bcl6 to repress target genes. Overall, we conclude that Stat3 is required to fine-tune the expression of multiple key genes in T-FH cells, and that the specific immune environment determines the function of Stat3 in T-FH cells.