The impact of cellular localization and migration on T cell differentiation during chronic infection 4169

Abstract Description Cellular localization is an integral aspect of T cell differentiation, reflecting the diverse roles and functions of distinct subsets. Virus-specific CD8+ T cells during chronic infection comprise subsets with distinct anatomical locations: effector cells (TEFF) are predominantly found in circulation, while terminally exhausted cells (TEXH) reside in tissues. Key questions arise: How does cellular localization integrate into differentiation programs, and can these programs be manipulated to influence cell-fate decisions? We hypothesize that cellular localization directly influences CD8+ T cell differentiation, with migratory and resident programs shaping effector and exhaustion outcomes, respectively. Using single-cell multiomic analyses, we identified KLF2 and KLF3 as key regulators of localization and differentiation. Genetic deletion of KLF2 impaired migration and TEFF differentiation, whereas KLF3 suppressed KLF2 activity via a feed-forward loop, promoting tissue retention and restricting TEFF differentiation. Importantly, restricting CD8+ T cells to circulation via S1PR1 overexpression or CD69 deletion enhanced TEFF differentiation, demonstrating that cellular localization not only reflects but also regulates CD8+ T cell differentiation during chronic infection. This insight provides a novel perspective on how migratory and resident programs influence antiviral immunity and T cell exhaustion. Funding Sources Supported by R01 AI148403/AI/NIAID NIH HHS/United States. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)