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Mutual inhibition between Prkd2 and Bcl6 controls T follicular helper cell differentiation

Prkd2-dependent phosphorylation of Bcl6 inhibits TFH cell differentiation. Kinase-regulated TFH differentiation The Bcl6 transcription factor plays a key role in directing the differentiation of T follicular helper cells (TFH) that support B cell antibody production and germinal center (GC) formation. Misawa et al. used a genetic screen in mice to identify a mutation in protein kinase D2 (Prkd2), a serine/threonine kinase, which resulted in enhanced basal and post-immunization levels of serum IgE. Mice with the Prkd2 mutation and Prkd2-deficient mice developed hypergammaglobulinemia and anti-DNA antibodies due to a T cell–intrinsic defect causing TFH expansion and an increase in GCs. Phosphorylation of Bcl6 by Prkd2 inhibited Bcl6 nuclear translocation and TFH differentiation. These findings provide fresh insight into the complex regulatory pathways controlling TFH differentiation by naïve T cells activated through their T cell receptor. T follicular helper cells (TFH) participate in germinal center (GC) development and are necessary for B cell production of high-affinity, isotype-switched antibodies. In a forward genetic screen, we identified a missense mutation in Prkd2, encoding the serine/threonine kinase protein kinase D2, which caused elevated titers of immunoglobulin E (IgE) in the serum. Subsequent analysis of serum antibodies in mice with a targeted null mutation of Prkd2 demonstrated polyclonal hypergammaglobulinemia of IgE, IgG1, and IgA isotypes, which was exacerbated by the T cell–dependent humoral response to immunization. GC formation and GC B cells were increased in Prkd2−/− spleens. These effects were the result of excessive cell-autonomous TFH development caused by unrestricted Bcl6 nuclear translocation in Prkd2−/− CD4+ T cells. Prkd2 directly binds to Bcl6, and Prkd2-dependent phosphorylation of Bcl6 is necessary to constrain Bcl6 to the cytoplasm, thereby limiting TFH development. In response to immunization, Bcl6 repressed Prkd2 expression in CD4+ T cells, thereby committing them to TFH development. Thus, Prkd2 and Bcl6 form a mutually inhibitory positive feedback loop that controls the stable transition from naïve CD4+ T cells to TFH during the adaptive immune response.