Spatial and functional diversity of innate lymphoid cells in the human female genital tract coordinates antiviral mucosal responses to HIV 3996

Abstract Description Innate lymphoid cells (ILCs) play a key role in the mucosal innate immune system, particularly in cytokine production. While studies in mice have shown that ILCs are involved in epithelial barrier maintenance and pathogen protection, their role in human mucosal immunity, especially in the female genital tract (FGT), has yet to be fully explored. Here, we characterized genital ILC subpopulations from human hysterectomy samples (endometrium, endocervix, and ectocervix) using spectral flow cytometry, CITE-seq, and ChipCytometry for spatial analysis, and assessed their response to HIV stimulation. Our results reveal novel compartmentalization of genital ILC subsets, with CD161 and NKp44 following opposite expression patterns that distinguish functional states both at steady-state and in response to HIV. At rest, CD161+ ILC3s were enriched for IL-22, and CD161- ILC1s for IFN-g. In contrast, NKp44 was linked to degranulation and identified ILC3s in lymphoid aggregates in the endometrium. Following HIV stimulation, genital ILCs mounted an antiviral response within 30 minutes via transcriptional changes. CD161 expression predicted cytokine secretion (IFN-g and IL-22) in preloaded ILCs and was downregulated after stimulation, while NKp44 was upregulated. These findings highlight the unique role of human genital ILCs in mucosal protection prior to and following viral stimulation. Funding Sources NIH R01AG060801 (MRG) R21AI172065 (MRG) U01AG084766 (MRG) Burroughs Welcome Fund PATH award (1334236) (MRG) Topic Categories Mucosal and Regional Immunology (MUC)