Memory-phenotype (MP) CD4+ T lymphocytes develop from naïve cells via self-recognition at homeostasis. While previous studies defined MP cells as a heterogeneous population that comprises T helper 1 (TH1)/17–like subsets, functional significance of the T-bet− Rorγt− subpopulation remains unknown. Here we show that MP lymphocytes as a whole population can differentiate into TH1/17/regulatory T (Treg) cells to mediate mild and persistent inflammation in lymphopenic environments, whereas naïve cells exhibit strong, TH1-dominated responses. Moreover, we demonstrate that MP lymphocytes comprise not only TH1/17-differentiated subsets but a polyclonal, transcriptomically immature “undifferentiated” subpopulation at homeostasis. Furthermore, our data argue that while the T-bet+ Rorγt− MP subset is terminally TH1-differentiated, its undifferentiated counterpart retains the capacity to rapidly proliferate to differentiate into TH1/17/Treg cells, with the latter response tonically constrained by preexisting Treg cells. Together, our results identify undifferentiated MP CD4+ T lymphocytes as a unique precursor that has a diverse differentiation potential to generate TH1/17/Treg cells to contribute to pathogenesis of inflammation.
We sincerely acknowledge E. M. Shevach and D. Jankovic [NIAID, National Institutes of Health (NIH)] for critical reading of the manuscript. In addition, we are grateful to G. J. H\u00E4mmerling (German Cancer Research Center) and S. Hori (The University of Tokyo) for Foxp3-DTR mice and C. S. Hsieh (Washington University School of Medicine) for support on TCR sequencing analysis. We also thank T. Nishina, Y. Okuyama, A. Asao, and Biomedical Research Core (Tohoku University Graduate School of Medicine) for technical assistance. This work was supported by the Japan Society for the Promotion of Science (T.K.: 20K16272, 20KK0362, 22H02884, 23K24146, 22K19418, 23H04761), Astellas Foundation for Research on Metabolic Disorders, Cell Science Research Foundation, Chemo-Sero-Therapeutic Research Institute, Chugai Foundation for Innovative Drug Discovery Science, Daiichi Sankyo Foundation of Life Science, Gonryo Foundation for the Promotion of Medical Science, G-7 Scholarship Foundation, Harmonic Ito Foundation, Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, Inamori Foundation, Intelligent Cosmos Foundation, Japan Allergy Foundation, Japan Intractable Diseases Research Foundation, Japan Rheumatism Foundation, Kanae Foundation for the Promotion of Medical Science, Kato Memorial Trust for Nambyo Research, Kobayashi Foundation, Kowa Life Science Foundation, Life Science Foundation of Japan, Mitsubishi Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, MSD Life Science Foundation, Naito Foundation, Nakajima Foundation, Nakayama Foundation for Human Science, Ohyama Health Foundation, Okinaka Memorial Institute for Medical Research, Pharmacodynamics Research Foundation, Senri Life Science Foundation, Senshin Medical Research Foundation, Sumitomo Foundation, Takeda Science Foundation, Ube Industries Foundation, Uehara Memorial Foundation, and Waksman Foundation of Japan. In addition, T.K. received funding from Bristol-Myers Squibb and GlaxoSmithKline. The funders were not involved in the study design, collection, analysis, interpretation of the data, writing of this article, or the decision to submit it for publication. A.K. was supported by the PhD Scholarship (Kibou Project) from Japanese Society for Immunology. This work was supported in part by the Intramural Research Program of the NIAID, NIH.
