Bhlhe40 Promotes CD4+ T Helper 1 Cell and Suppresses T Follicular Helper Cell Differentiation during Viral Infection. J Immunol 2024 Jun 01;212(11):1829-1842
Date
04/15/2024Pubmed ID
38619295DOI
10.4049/jimmunol.2300355Scopus ID
2-s2.0-85194012903 (requires institutional sign-in at Scopus site)Abstract
In response to acute infection, naive CD4+ T cells primarily differentiate into T helper 1 (Th1) or T follicular helper (Tfh) cells that play critical roles in orchestrating cellular or humoral arms of immunity, respectively. However, despite the well established role of T-bet and BCL-6 in driving Th1 and Tfh cell lineage commitment, respectively, whether additional transcriptional circuits also underlie the fate bifurcation of Th1 and Tfh cell subsets is not fully understood. In this article, we study how the transcriptional regulator Bhlhe40 dictates the Th1/Tfh differentiation axis in mice. CD4+ T cell-specific deletion of Bhlhe40 abrogates Th1 but augments Tfh differentiation. We also assessed an increase in germinal center B cells and Ab production, suggesting that deletion of Bhlhe40 in CD4+ T cells not only alters Tfh differentiation but also their capacity to provide help to B cells. To identify molecular mechanisms by which Bhlhe40 regulates Th1 versus Tfh lineage choice, we first performed epigenetic profiling in the virus specific Th1 and Tfh cells following LCMV infection, which revealed distinct promoter and enhancer activities between the two helper cell lineages. Furthermore, we identified that Bhlhe40 directly binds to cis-regulatory elements of Th1-related genes such as Tbx21 and Cxcr6 to activate their expression while simultaneously binding to regions of Tfh-related genes such as Bcl6 and Cxcr5 to repress their expression. Collectively, our data suggest that Bhlhe40 functions as a transcription activator to promote Th1 cell differentiation and a transcription repressor to suppress Tfh cell differentiation.
Author List
Nguyen C, Kudek M, Zander R, Niu H, Shen J, Bauer A, Alson D, Khatun A, Chen Y, Sun J, Drobyski W, Edelson BT, Cui WAuthors
Donia Alson Postdoctoral Researcher 1 in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinWilliam R. Drobyski MD Professor in the Medicine department at Medical College of Wisconsin
Matthew Kudek MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsB-Lymphocytes
Basic Helix-Loop-Helix Transcription Factors
Cell Differentiation
Germinal Center
Homeodomain Proteins
Lymphocytic Choriomeningitis
Lymphocytic choriomeningitis virus
Mice
Mice, Inbred C57BL
Mice, Knockout
Proto-Oncogene Proteins c-bcl-6
Receptors, CXCR5
Th1 Cells
