The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development
Open Access
- 29 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Immunology
- Vol. 21 (9), 1082-1093
- https://doi.org/10.1038/s41590-020-0713-6
Abstract
Memory B cells (MBCs) are essential for long-lived humoral immunity. However, the transcription factors involved in MBC differentiation are poorly defined. Here, using single-cell RNA sequencing analysis, we identified a population of germinal center (GC) B cells in the process of differentiating into MBCs. Using an inducible CRISPR–Cas9 screening approach, we identified the hematopoietically expressed homeobox protein Hhex as a transcription factor regulating MBC differentiation. The corepressor Tle3 was also identified in the screen and was found to interact with Hhex to promote MBC development. Bcl-6 directly repressed Hhex in GC B cells. Reciprocally, Hhex-deficient MBCs exhibited increased Bcl6 expression and reduced expression of the Bcl-6 target gene Bcl2. Overexpression of Bcl-2 was able to rescue MBC differentiation in Hhex-deficient cells. We also identified Ski as an Hhex-induced transcription factor involved in MBC differentiation. These findings establish an important role for Hhex–Tle3 in regulating the transcriptional circuitry governing MBC differentiation.Keywords
Funding Information
- Howard Hughes Medical Institute (DRG-2265-16)
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (T32AI07019)
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (R01AI040098, R01AI045073, R01AI045073, R01AI045073)
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