학술논문
The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development
Document Type
Report
Source
Nature Immunology. September 2020, Vol. 21 Issue 9, p1082, 12 p.
Subject
Language
English
ISSN
1529-2908
Abstract
Author(s): Brian J. Laidlaw [sup.1] [sup.2] [sup.4] , Lihui Duan [sup.1] [sup.2] , Ying Xu [sup.1] [sup.2] , Sara E. Vazquez [sup.1] [sup.3] , Jason G. Cyster [sup.1] [sup.2] Author [...]
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. Generation of memory B cells is crucial for protective immunity to infectious agents. Cyster and colleagues show that the transcription factor Hhex interacting with Tle3 promotes memory B cell generation.
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. Generation of memory B cells is crucial for protective immunity to infectious agents. Cyster and colleagues show that the transcription factor Hhex interacting with Tle3 promotes memory B cell generation.