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

Takuma Misawa, Jeffrey A. SoRelle, Jin Huk Choi, Tao Yue, Kuan Wen Wang, William McAlpine, Jianhui Wang, Aijie Liu, Koichi Tabeta, Emre E. Turer, Bret Evers, Evan Nair-Gill, Subhajit Poddar, Lijing Su, Feiya Ou, Liyang Yu, Jamie Russell, Sara Ludwig, Xiaoming Zhan, Sara HildebrandXiaohong Li, Miao Tang, Anne R. Murray, Eva Marie Y. Moresco, Bruce Beutler

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalScience Immunology
Volume5
Issue number43
DOIs
StatePublished - Jan 24 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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