CD8+ T cells are key players in HIV control and future cure efforts. Current knowledge of HIV-specific CD8+ T cells relies almost entirely on circulating cells, although HIV is primarily a disease of lymphoid tissue. Accumulating evidence indicates that non-circulating ‘resident memory’ (TRM) CD8+ T cell responses are critical for pathogen control in tissues; however, whether CD8+ TRMs are found in lymphoid tissue is uncertain. Conceptually, most lymphoid memory CD8+ T cells are thought to recirculate, but such data are based on human blood and hygienic mouse models.
Human peripheral blood and lymphoid tissues from multiple locations were collected from healthy controls and HIV-infected subjects, including ART-, ART+, and elite controllers from different sites in North and Central America. Peripheral blood and lymph nodes were also compared between laboratory mice living in ultra-hygienic specific-pathogen free (SPF) environment and ‘dirty’ mice that had more physiologic infectious experience. Multi-parametric flow cytometry, histo-cytometry, gene expression, and tetramer analysis were used to assess the localization, phenotype, and transcriptional profile of CD8+ T cells. Data were analyzed in FlowJo, GraphPad Prism, and R Studio.
We here provide evidence that a majority of memory CD8+ T cells in lymphoid tissue of healthy humans bear a TRM phenotype, with high expression of CD69 and variable levels of CD103. Furthermore, ‘dirty’ mice exhibited substantially more of the TRM phenotype within lymph nodes than SPF mice. Lymphoid TRMs are detectable in HIV-infected lymph nodes using histo-cytometry and most CD8+ T cells with B cell follicle homing potential (CXCR5+) have a TRM phenotype. Importantly, the majority of HIV-specific CD8+ T cells in lymph nodes are TRMs and show transcriptional and phenotypic characteristics that are distinct from peripheral blood HIV-specific CD8+ T cells. Finally, we find that HLA-B57/27+ elite controllers demonstrate high magnitudes of HIV-specific TRMs in lymph nodes that selectively target immunodominant epitopes within Gag.
We identify that HIV-specific TRMs are the front-line defense in HIV-infected lymph nodes. TRMs do not share the same phenotypic and transcriptional characteristics with circulating HIV-specific CD8+ T cells that have classically been studied in the context of HIV pathogenesis. Elicitation of functional and high numbers of lymphoid CD8+ TRMs should be a priority for any HIV vaccine or eradication strategy.