Roles of Bcl6 and Blimp1 in CD4 T follicular helper (Tfh) lineage commitment (99.11)

Abstract

Abstract A distinct CD4 effector T cell subset, called T follicular helper cells (Tfh), is required for proper B cell responses in vivo. The mutually antagonistic transcription factors Bcl6 and Blimp1 play central but opposing roles in Tfh differentiation (Johnston et al., Science 2009). Bcl6 is both necessary and sufficient for in vivo Tfh differentiation, while Blimp1 specifically inhibits it. Expression of both Bcl6 and Blimp1, controlled temporally and spatially by cell-cell contact and multiple cytokines, is necessary for a normal CD4 T cell response. Naïve CD4 T cells express Bcl6 mRNA prior to, and independent of, commitment to the Tfh lineage. Bcl6 contains multiple functional domains and can affect different transcriptional outcomes depending on the local chromatin and co-repressor environment. Bcl6 repression of Blimp1 requires the co-repressor MTA3, which binds the Bcl6 RDII domain. We show that a loss of function mutation in the Bcl6 RDII domain results in a total failure of CD4 T cells to proliferate in vivo following infection with LCMV. We posit that this proliferation defect is a result of the failure to control expression of Blimp1, a strongly anti-proliferative protein, immediately following activation. Conversely, failure to attain adequate Blimp1 expression also results in an abnormal antiviral CD4 T cell response. Taken together, our findings suggest that the roles of Bcl6 and Blimp1 in CD4 T cells extend beyond Tfh lineage commitment.