Transcription factor Bhlhe40 plays a protective role during intravaginal Chlamydia muridarum infection in mice

Abstract The protein basic helix-loop-helix family member e40 (BHLHE40) is a transcription factor involved in cell cycle regulation and differentiation. It has recently emerged as a key player in immunity regulating T cell responses and cytokine production during infections. To address the role of Bhlhe40in Chlamydiainfections, we infected WT and Bhlhe40−/−mice intravaginally with Chlamydia muridarumand monitored infection kinetics. Bhlhe40−/−mice exhibited a significant defect in their ability to clear infection compared to their WT counterparts. Single-cell RNA sequencing revealed distinct heterogeneity in the CD4 +T cell population in the female reproductive tract in WT and Bhlhe40−/−mice following C. muridaruminfection. Accordingly, CD4 +T cell population in Bhlhe40−/−mice showed a marked increase in IL-10-producing T regulatory type 1 (Tr1) cells and decreased IFN-γ and GM-CSF-producing cells as assessed by flow cytometry. The overall CD4 +T cell cytokine response was diminished in the absence of Bhlhe40, as indicated by decreased levels of IFN-γ, GM-CSF and IL-17A measured by a multiplex cytokine assay. In contrast, Bhlhe40did not appear to play an essential role in antibody responses, development of pathology, or metabolic fitness of CD4 T cells during C. muridaruminfection. Lastly, IL-10 deficiency restored optimal bacterial clearance in Bhlhe40−/−mice. Altogether, our findings identified Bhlhe40as a novel player in protective immune response against C. muridaruminfection in mice. NIH/NIAID R01 (AI139124) NIH/NIGMS COBRE (GM103625)The American Association of Immunologists through a Careers in Immunology Fellowship