CD97-hi naive CD4 T cells are poised for Th1 responses and reflect inflammatory disease states 2249830

Abstract Introduction Naïve T cells have long been viewed as quiescent precursors with limited roles in disease pathogenesis. However, emerging evidence suggests functional diversity even within this population. Building on our recent findings, we aimed to define the phenotypic and functional relevance of CD97-hi naïve T cells in inflammatory diseases. Methods Single-cell transcriptomic and epigenomic analyses were performed to identify distinct naïve CD4 T cell subsets in humans and mice (approved by institutional IACUC and IRB). Functional characterization was conducted using in vitro primary mouse T cell cultures and in vivo cell transfer models. For humans, we analyzed publicly available single-cell datasets from various disease cohorts, and peripheral blood samples from healthy donors and patients were examined by flow cytometry to validate CD97-hi naïve CD4 T cells. Results Distinct CD97-hi naïve CD4 T cells expressing IL-18R under steady-state conditions were identified in both mice and humans. These cells exhibited strong Th1 differentiation potential, producing robust IFN-γ and showing increased chromatin accessibility at Th1-associated loci. In humans, these cells were significantly enriched in responders to anti—PD-1 therapy as well as in patients with multiple sclerosis, COVID-19, systemic lupus erythematosus, and common variable immunodeficiency, with their frequency correlating with disease states. Conclusion CD97-hi naïve CD4 T cells represent functionally distinct cells capable of sensing and reflecting inflammatory cues and are primed for Th1-type effector responses. Their frequency strongly correlates with multiple inflammatory and immune-mediated diseases, highlighting an unconventional view of naïve T cells–not as passive precursors but as active contributors and potential biomarkers. Funding Source Basic Science Research Program of the National Research Foundation funded by the Korean Government (RS-2024-00334289), Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (RS-2024-004 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)