Naïve CD4 T cells are traditionally viewed as a quiescent, homogeneous, resting population, but emerging 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 contributes to the inhibition of cancer progression in B16F10 tumor-bearing mice. In humans, this IL-7Rsup-hi subpopulation expressing CD97 correlates with the responsiveness to anti-PD-1 therapy in cancer patients and the disease state of multiple sclerosis. By elucidating the heterogeneity of naive CD4 T cells and identifying 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.
© 2025. The Author(s).