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

Foxp3+ regulatory T (Treg) cells are essential to maintain immune homeostasis, yet controversy exists about the stability of this cell population. Bcl6-deficient (Bcl6−/−) mice develop severe and spontaneous T helper type 2 (Th2) inflammation and Bcl6-deficient Treg cells are ineffective at controlling Th2 responses. We used a lineage tracing approach to analyse the fate of Treg cells in these mice. In the periphery of Bcl6−/− mice, increased numbers of Foxp3-negative 'exTreg' cells were found, particularly in the CD25+ population. ExTreg cells from Bcl6−/− mice expressed increased interleukin-17 ( IL-17) and extremely elevated levels of Th2 cytokines compared with wild-type exTreg cells. Although Treg cells normally express only low levels of cytokines, Treg cells from Bcl6−/− mice secreted higher levels of IL-4, IL-5, IL-13 and IL-17 than wild-type conventional T cells. Next, Treg-specific conditional Bcl6-deficient (Bcl6Foxp3−/−) mice were analysed. Bcl6Foxp3−/− mice do not develop inflammatory disease, indicating a requirement for non-Treg cells for inflammation in Bcl6−/− mice, and have normal numbers of exTreg cells. We induced Th2-type allergic airway inflammation in Bcl6Foxp3−/− mice, and found that while exTreg cytokine expression was normal, Bcl6-deficient Treg cells expressed higher levels of the Th2-specific regulator Gata3 than Bcl6+ Treg cells. Bcl6Foxp3−/− mice had increased numbers of Th2 cells after induction of airway inflammation and increased T cells in the bronchoalveolar lavage fluid. These data show both Treg-intrinsic and Treg-extrinsic roles for Bcl6 in controlling Treg cell stability and Th2 inflammation, and support the idea that Bcl6 expression in Treg cells is critical for controlling Th2 responses. [ABSTRACT FROM AUTHOR]