Sensing and alarm function of vaccineelicited SIV-gag specific CD8 T-RM in the reproductive mucosa of rhesus macaques

Abstract Resident memory T cells (TRM) constitute a recently identified lymphocyte lineage that occupies non-lymphoid tissues (NLT) without recirculating. In murine models, upon antigenic rechallenge, TRM trigger antiviral responses in neighboring innate and adaptive immune cells, and recruit immune effectors from circulation. Collectively this is referred to as a ‘sensing and alarm’ function. However, the full range of TRM functions has not been assessed, and non-human primate/human TRM function remains almost entirely uncharacterized. Here we established a prime-boost vaccine modality in rhesus macaques to generate abundant SIV-gag-specific CD8 TRM in the female reproductive tract (FRT) and 14 other NLTs. Upon vaginal challenge with CM9 peptide from the SIV gag protein, CD8 TRM reactivation induced expression of CD69 and granzyme B in SIV-gag specific CD8 T cells throughout the rhesus FRT, in situ proliferation (Ki67 expression), and rapid antiviral and IFN response gene expression in essentially all hematopoietic and non-hematopoietic cells. Upregulation of effector genes in CD8 T cells, CD4 T cells, NK cells, and ILCs peaked at 24h and persisted at 48h. CITE-Seq analysis revealed that mucosal CD4 T cells expressed antiviral genes including HIV restriction factors and had reduced expression of the HIV-co-receptor CCR5. Increased numbers of vaginal T cells, memory B cells, and plasma cells at 24h coincided with increased expression of chemokines and VCAM-1 on endothelial and stromal cells and a concomitant reduction in circulating T and B cells. These data demonstrate that CD8 TRM trigger local activation and the mobilization of innate, cellular, and humoral immune responses to the site of antigen exposure in non-human primates.