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

Jae-Won Yoon, Kyung Min Kim, Sookyung Cho, Min-Ji Cho, Seonjun Park, Daehee Hwang, Hye Ryun Kim, Sung Ho Park, Jae-Ho Cho, Hyobin Jeong () and Je-Min Choi ()
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Jae-Won Yoon: Hanyang University
Kyung Min Kim: Seoul National University
Sookyung Cho: Hanyang University
Min-Ji Cho: Hanyang University
Seonjun Park: Ulsan National Institute of Science & Technology (UNIST)
Daehee Hwang: Seoul National University
Hye Ryun Kim: Yonsei Cancer Center Yonsei University College of Medicine
Sung Ho Park: Ulsan National Institute of Science & Technology (UNIST)
Jae-Ho Cho: Chonnam National University Medical School
Hyobin Jeong: Yonsei University
Je-Min Choi: Hanyang University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57237-3

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