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Mutual inhibition between Prkd2 and Bcl6 controls T follicular helper cell differentiation. 2020
Takuma Misawa, and
Jeffrey A SoRelle, and
Jin Huk Choi, and
Tao Yue, and
Kuan-Wen Wang, and
William McAlpine, and
Jianhui Wang, and
Aijie Liu, and
Koichi Tabeta, and
Emre E Turer, and
Bret Evers, and
Evan Nair-Gill, and
Subhajit Poddar, and
Lijing Su, and
Feiya Ou, and
Liyang Yu, and
Jamie Russell, and
Sara Ludwig, and
Xiaoming Zhan, and
Sara Hildebrand, and
Xiaohong Li, and
Miao Tang, and
Anne R Murray, and
Eva Marie Y Moresco, and
Bruce Beutler
Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, TX 75390, USA. takuma.misawa@utsouthwestern.edu bruce.beutler@utsouthwestern.edu.
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.
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