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

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.

• Authors: 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 Hildebrand, Xiaohong Li, Miao Tang, Anne R Murray, Eva Marie Y Moresco, Bruce Beutler
• Journal: Science immunology (Sci Immunol) Vol. 5 Issue 43 (01 24 2020) ISSN: 2470-9468 [Electronic] United States
• PMID: 31980486 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Bcl6 protein, mouse
• Immunoglobulins
• Protein Kinase D2
• Proto-Oncogene Proteins c-bcl-6
• Protein Kinases

Topics

• Animals
• B-Lymphocytes (immunology)
• Bone Marrow Transplantation
• CD4-Positive T-Lymphocytes (immunology)
• Cell Differentiation
• Female
• Germinal Center (immunology)
• HEK293 Cells
• Humans
• Immunoglobulins (blood)
• Immunotherapy, Adoptive
• Male
• Mice, Transgenic
• Mutation
• Protein Kinase D2
• Protein Kinases (genetics, immunology)
• Proto-Oncogene Proteins c-bcl-6 (immunology)