Molecular heterogeneity of antiviral resident memory CD8 T cell in the female reproductive tract

Resident memory CD8 T cells (TRM) in the female reproductive tract (FRT) represent a primary defense mechanism against viruses. Presence of CD8 TRM in the reproductive mucosa is associated with accelerated viral control and rapid establishment of an antiviral state. However, little is known about the factors that control and maintain TRM in this important barrier organ. Here, using single-cell RNA-sequencing (scRNA-seq) and genetic methods, we characterized development of distinct FRT CD8 TRM subsets. Our scRNA-seq studies revealed that most FRT CD8 TRM belong to two transcriptionally distinct subsets that are marked by mutually exclusive surface expression of CD103 and Ly6C. CD103 +TRM were dependent on the cytokine TGF-b for development, as CD8 T cells lacking TGF-b receptors were significantly impaired at giving rise to CD103 +TRM. Local activation of TGF-b by av integrins was important for the maintenance of these FRT TRM. In comparison to the CD103 +TRM which resembled mature TRM, the Ly6C +TRM exhibited features of effector cells. Ly6C +TRM were regulated by the transcription factor T-bet and developed under distinct priming conditions compared to CD103 +TRM. Upon in vivo antigenic recall, the CD103 +subset elaborated greater cytotoxicity than the Ly6C +subset. Taken together, our findings provide key insights into molecular and developmental heterogeneity of FRT CD8 TRM which has implications for improving vaccination and local immunotherapy approaches. Supported by grants from NIH (P20GM121298)