A fundamental function of CD4 + helper T (T H ) cells is the regulation of B cell-mediated humoral immunity. Development of T follicular helper (T FH ) cells that provide help to B cells is mediated by the cytokines interleukin-6 and interleukin-21 but is independent of T H 1, T H 2, and T H 17 effector cell lineages. Here, we characterize the function of Bcl6, a transcription factor selectively expressed in T FH cells. Bcl6 expression is regulated by interleukin-6 and interleukin-21. Bcl6 overexpression induced T FH -related gene expression and inhibited other T H lineage cell differentiation in a DNA binding-dependent manner. Moreover, Bcl6 deficiency in T cells resulted in impaired T FH cell development and germinal center reactions, and altered production of other effector T cell subsets. Our data thus illustrate that Bcl6 is required for programming of T FH cell generation.

Foxp3+ regulatory T (Treg) cells suppress different types of immune responses to help maintain homeostasis in the body. How Treg cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of Treg cells expressing CXCR5 and Bcl6, and localized in the germinal centers in mouse as well as human. The expression of CXCR5 on Treg cells depends on Bcl6. These CXCR5+Bcl6+ Treg cells are absent in thymus but can be de novo generated from CXCR5-Foxp3+ natural Treg precursors. Lack of CXCR5+ Treg cells leads to greater germinal center reactions. These results unveil a Bcl6-CXCR5 axis in Treg cells that undermines the development of follicular regulatory T (Tfr) cells that function to inhibit the germinal center reaction.

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This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.