BHLHE40 drives protective polyfunctional CD4 T cell differentiation in the female reproductive tract againstChlamydia

Abstract

AbstractThe protein basic helix-loop-helix family member e40 (BHLHE40) is a transcription factor recently emerged as a key regulator of host immunity to infections, autoimmune diseases and cancer. In this study, we investigated the role ofBhlhe40in protective T cell responses to the intracellular bacteriumChlamydiain the female reproductive tract (FRT). Mice deficient inBhlhe40exhibited severe defects in their ability to controlChlamydia muridarumshedding from the FRT. The heightened bacterial burdens inBhlhe40−/−mice correlated with a marked increase in IL-10-producing T regulatory type 1 (Tr1) cells and decreased polyfunctional CD4 T cells co-producing IFN-γ, IL-17A and GM-CSF. Genetic ablation of IL-10 or functional blockade of IL-10R increased CD4 T cell polyfunctionality and partially rescued the defects in bacterial control inBhlhe40−/−mice. Using single-cell RNA sequencing coupled with TCR profiling, we detected a significant enrichment of stem-like T cell signatures inBhlhe40-deficient CD4 T cells, whereas WT CD4 T cells were further down on the differentiation trajectory with distinct effector functions beyond IFN-γ production by Th1 cells. Altogether, we identifiedBhlhe40as a key molecular driver of CD4 T cell differentiation and polyfunctional responses in the FRT againstChlamydia.