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BHLHE40 drives protective polyfunctional CD4 T cell differentiation in the female reproductive tract against Chlamydia.

ABSTRACT: The 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 of Bhlhe40 in protective T cell responses to the intracellular bacterium Chlamydia in the female reproductive tract (FRT). Mice deficient in Bhlhe40 exhibited severe defects in their ability to control Chlamydia muridarum shedding from the FRT. The heightened bacterial burdens in Bhlhe40 ^-/- 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 in Bhlhe40 ^-/- mice. Using single-cell RNA sequencing coupled with TCR profiling, we detected a significant enrichment of stem-like T cell signatures in Bhlhe40 -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 identified Bhlhe40 as a key molecular driver of CD4 T cell differentiation and polyfunctional responses in the FRT against Chlamydia .

SUBMITTER: Mercado MAB

PROVIDER: S-EPMC10635079 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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BHLHE40 drives protective polyfunctional CD4 T cell differentiation in the female reproductive tract against Chlamydia.

Mercado Miguel A B MAB Li Qiang Q Quick Charles M CM Kim Yejin Y Palmer Rachel R Huang Lu L Li Lin-Xi LX

bioRxiv : the preprint server for biology 20231105

The 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 of Bhlhe40 in protective T cell responses to the intracellular bacterium Chlamydia in the female reproductive tract (FRT). Mice deficient in Bhlhe40 exhibited severe defects in their ability to control Chlamydia muridarum shedding from the FRT ...[more]

PMID: 37961221

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Project description:BackgroundChlamydia trachomatis and Mycoplasma infections have been regarded as severe challenges to public health worldwide because their potential risk of leading to serious reproductive complications. C. trachomatis is the most common sexually transmitted bacterial infections and the prevalence has been increasing in recent years. As a newly discovered pathogen, Mycoplasma genitalium has gradually been recognized as important sexually transmitted infection and even been called a "new chlamydia". There are no official epidemiological data of M. genitalium in China especially in women with lower reproductive tract infection. This work aims to understand the prevalence and risk factors of M. genitalium and C. trachomatis in women with lower reproductive tract infections and to provide reference for the formulation of health policy in China.MethodsThis study was conducted in the gynecological clinics of 12 hospitals geographically located in different regions in China. Women with purulent cervical secretions or abnormal vaginal microecology were included as the research group, and those with normal vaginal microecology and cervical secretions were included as the control group. A total of 2190 participants were recruited in this project including 1357 of research group and 833 of control group. All participants were required to complete questionnaires, whose vaginal discharge were collected for vaginal microecology test and cervical discharge for detection of M. genitalium and C. trachomatis.ResultsThe prevalence of C. trachomatis and M. genitalium were 7.1% (96/1357) and 3.8% (51/1357), respectively in research group. The prevalence of C. trachomatis and M. genitalium varied in different regions. Infection rates of C. trachomatis and M. genitalium were higher in women with abnormal vaginal microecology (C.t P = 0.038, M.g P = 0.043), especially in women with bacterial vaginosis and mixed vaginitis, of which C. trachomatis showed statistical differences (bacterial vaginosis, P = 0.035; mixed vaginitis, P = 0.0001) and M. genitalium was close to statistical differences (bacterial vaginosis, P = 0.057; mixed vaginitis, P = 0.081). Alcoholism and abnormal vaginal microecology were positively correlated with both C. trachomatis and M. genitalium infection. Increasing age, being married and multi-parity were negatively correlated with C. trachomatis infection. There is a positive correlation between multiple sexual partners, diversed styles of sex and C. trachomatis infection.ConclusionsWomen with lower genital dysbiosis have an increased risk of C. trachomatis and M. genitalium. The overall prevalence of M. genitalium is lower than that of C. trachomatis, while they have similarities in the characteristics of infection. Although M. genitalium is not routinely screened as C. trachomatis in young women, attention should be paid to M. genitalium infection in young women with abnormal vaginal microecology or having childbearing needs.

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BHLHE40 drives protective polyfunctional CD4 T cell differentiation in the female reproductive tract against Chlamydia.

Publications

BHLHE40 drives protective polyfunctional CD4 T cell differentiation in the female reproductive tract against <i>Chlamydia</i>.

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