Diverse Microbial Exposure Enhances CD8+ T Cell Effector Memory Output and Function 2310008

Abstract

Abstract Introduction Mice with normalized microbial exposure (NME) harbor an immune system that more accurately reflects that of humans compared to mice maintained in specific pathogen-free (SPF) facilities. When comparing the immune compartment of NME mice to SPF controls, major shifts are observed in many different immune cell subsets, including expansion of activated T cells. A mechanism for the observed alterations in the composition of the T cell compartment in NME mice has not been reported. Thus, in collaboration with immgenT, we set out to profile the T cell compartment of NME mice on a single cell level. Methods Here, we compared the splenic T cell landscape in NME versus SPF mice at baseline and after acute LCMV infection via single cell RNA sequencing. Additionally, we compared immune cell populations from the blood of mice with increasing levels of NME conversion. We then confirmed the changes we saw in our sequencing data with flow cytometry and adoptive transfers. Results Using the immgenT dataset as a reference, we found that there are no new T cell populations in NME, but the landscape shifts towards more activated T cells with increased propensity for effector functions and improved pathogen clearance capacity. In particular, CD8+ KLRG1+ long-lived effector T cells are significantly expanded in NME mice and showed increased cytokine production. The shift to long lived effector T cells in NME mice is a result of increased formation and the conversion of other memory populations. Conclusion By leveraging the immgenT atlas we characterized T cells from the spleen and blood of NME mice, providing insight into the compositional and functional differences between SPF and NME mouse T cell compartments. We found improved LLEC function and pathogen clearance by NME-derived T cells. Finally, we showed that the numeric shifts in T cell populations in NME are likely to be promoted by continued inflammatory cues rather than only antigenic stimulation. Funding Source n/a Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)