TGF-β signaling is important for female reproductive tract resident memory CD8 T cell development

Abstract Tissue-resident memory T cells (TRM) patrol non-lymphoid barrier tissues and provide rapid protection against reinvading pathogens. While TRM formation in several barrier mucosal tissues including intestine and respiratory tract has been investigated, factors that control TRM establishment in the female reproductive tract (FRT) remain unclear. Here we established a model of local FRT infection, characterized CD8 TRM development and probed the role of cytokine TGF-β in TRM formation. We adopted a mouse model of intravaginal lymphocytic choriomeningitis virus (LCMV) infection that generated robust local CD8 T cell response in both the lower FRT (cervix, vagina) and upper FRT (ovaries and uterine horn). Upon viral clearance, CD8 T cells in the tissue gradually adopted mature TRM phenotype. Parabiosis confirmed most antiviral T cells in the FRT were truly resident. There were marked differences in the phenotypes of TRM in upper and lower FRT with CD103+ epithelial TRM predominating the lower FRT mucosa. Longitudinal analysis revealed TRM in both compartments undergoes attrition. The cytokine TGF-β has been implicated in TRM development in number of barrier and visceral organs. Using TGF-β RII deficient transgenic CD8 T cells, we observed that lack of TGF-β receptor signaling impairs acquisition of CD103 and CD69 expression by FRT TRM. However, TGF-β RII deficient CD8 T cells showed elevated expression of effector molecules granzyme-B and interferon-gamma upon in vivo stimulation. Taken together, our data suggest a key role of TGF-β in the formation and function of virus specific TRM in the FRT. Further investigation will provide mechanistic insight on the nature of TGF-β signaling pathway impacting FRT TRM formation. Supported by NIH grants (P20GM121298 and P20GM109035) and Searle Scholars Foundation