Th1-poised naïve CD4 T cell subpopulation reflects anti-tumor immunity and autoimmune disease

Naïve CD4 T cells are traditionally viewed as a quiescent, homogeneous, resting population, but merging evidence reveals their heterogeneity, which can be crucial for understanding disease contexts and therapeutic outcomes. In this study, we identify distinct subpopulations within both murine and human naïve CD4 T cells by single cell-RNA-sequencing (scRNA-seq), particularly focusing on a subpopulation that expresses super-high levels of interleukin-7 receptor (IL-7Rsup-hi), along with CD97, IL-18R, and Ly6C. This subpopulation, absent in the thymus and peripherally induced, exhibits type 1 helper T cell (Th1)-poised characteristics and plays a role in inhibiting cancer progression in mouse B16F10 tumor model. In humans, this IL-7Rsup-hi subpopulation expressing CD97 correlates with responsiveness to anti-PD-1 therapy in cancer patients and disease state of multiple sclerosis. By elucidating the heterogeneity of naive CD4 T cells, including a Th1-poised subpopulation capable of robust type 1 responses, we highlight the importance of this heterogeneity in inflammatory conditions for defining the disease states and predicting drug responsiveness.