Aging modifies endometrial dendritic cell function and unconventional double negative T cells in the human genital mucosa

• Published in: Immunity & ageing Vol. 20; no. 1; p. 34
• Main Authors: Parthasarathy, Siddharth, Shen, Zheng, Carrillo-Salinas, Francisco J, Iyer, Vidya, Vogell, Alison, Illanes, Diego, Wira, Charles R, Rodriguez-Garcia, Marta
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 14.07.2023; BioMed Central; BMC
• Subjects: Aging; Analysis; Antigens; Antiviral agents; Cancer; CD4 antigen; CD8 antigen; Cell growth; Cell proliferation; Chemokines; Cytokines; Cytotoxicity; Dendritic cells; Disease susceptibility; Endometrium; Flow cytometry; Genital tract; Gynecology; Health aspects; Immune response; Immune system; Immunology; Infection; Infections; Lymphocytes; Lymphocytes T; Menopause; Menstruation; Mucosa; Population; Pregnancy; Prevention; Reproductive failure; Resident memory T cells; Sexually transmitted diseases; Sexually transmitted infections; STD; T cells; TGF-β; Womens health; Resident memory T cells; Dendritic cells; Menopause; Single-cell sequencing; TGF-β; Double negative T cells; Endometrium; Sexually transmitted infections
• ISSN: 1742-4933; 1742-4933
• DOI: 10.1186/s12979-023-00360-w

Immune function in the genital mucosa balances reproduction with protection against pathogens. As women age, genital infections, and gynecological cancer risk increase, however, the mechanisms that regulate cell-mediated immune protection in the female genital tract and how they change with aging remain poorly understood. Unconventional double negative (DN) T cells (TCRαβ + CD4-CD8-) are thought to play important roles in reproduction in mice but have yet to be characterized in the human female genital tract. Using genital tissues from women (27-77 years old), here we investigated the impact of aging on the induction, distribution, and function of DN T cells throughout the female genital tract. We discovered a novel site-specific regulation of dendritic cells (DCs) and unconventional DN T cells in the genital tract that changes with age. Human genital DCs, particularly CD1a + DCs, induced proliferation of DN T cells in a TFGβ dependent manner. Importantly, induction of DN T cell proliferation, as well as specific changes in cytokine production, was enhanced in DCs from older women, indicating subset-specific regulation of DC function with increasing age. In human genital tissues, DN T cells represented a discrete T cell subset with distinct phenotypical and transcriptional profiles compared to CD4 + and CD8 + T cells. Single-cell RNA and oligo-tag antibody sequencing studies revealed that DN T cells represented a heterogeneous population with unique homeostatic, regulatory, cytotoxic, and antiviral functions. DN T cells showed relative to CD4 + and CD8 + T cells, enhanced expression of inhibitory checkpoint molecules and genes related to immune regulatory as well as innate-like anti-viral pathways. Flow cytometry analysis demonstrated that DN T cells express tissue residency markers and intracellular content of cytotoxic molecules. Interestingly, we demonstrate age-dependent and site-dependent redistribution and functional changes of genital DN T cells, with increased cytotoxic potential of endometrial DN T cells, but decreased cytotoxicity in the ectocervix as women age, with implications for reproductive failure and enhanced susceptibility to infections respectively. Our deep characterization of DN T cell induction and function in the female genital tract provides novel mechanistic avenues to improve reproductive outcomes, protection against infections and gynecological cancers as women age.