Excess generation and activation of naturally arising memory-phenotype CD4+ T lymphocytes are inhibited by regulatory T cells in steady state

Jing Li; Ziying Yang; Akihisa Kawajiri; Kosuke Sato; Shunichi Tayama; Naoto Ishii; Jinfang Zhu; Takeshi Kawabe

doi:10.3389/fimmu.2024.1429954

Excess generation and activation of naturally arising memory-phenotype CD4⁺ T lymphocytes are inhibited by regulatory T cells in steady state

Front Immunol. 2024 Aug 16:15:1429954. doi: 10.3389/fimmu.2024.1429954. eCollection 2024.

Authors

Jing Li¹, Ziying Yang¹, Akihisa Kawajiri¹, Kosuke Sato¹, Shunichi Tayama¹, Naoto Ishii¹, Jinfang Zhu², Takeshi Kawabe^{1

2}

Affiliations

¹ Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
² Molecular and Cellular Immunoregulation Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.

Abstract

Conventional CD4⁺ T lymphocytes consist of naïve, foreign antigen-specific memory, and self-antigen-driven memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells tonically proliferate in response to self-antigens and differentiate into the T-bet⁺ subset in steady state. How excess proliferation and differentiation of MP cells are inhibited remains unclear. Given immunosuppressive function of regulatory T cells (Tregs), it is possible that they are also involved in inhibition of spontaneous MP cell activation. Here we show using Foxp3-diphtheria toxin receptor-transgenic mice that both MP and naïve CD4⁺ T cells spontaneously proliferate and differentiate into Th1 cells upon acute Treg depletion. At an early time point post Treg depletion, MP as compared to naïve CD4⁺ T cells are preferentially activated while at a later stage, the response is dominated by activated cells originated from the naïve pool. Moreover, we argue that MP cell proliferation is driven by TCR and CD28 signaling whereas Th1 differentiation mediated by IL-2. Furthermore, our data indicate that such activation of MP and naïve CD4⁺ T lymphocytes contribute to development of multi-organ inflammation at early and later time points, respectively, after Treg ablation. Together our findings reveal that Tregs tonically inhibit early, spontaneous proliferation and Th1 differentiation of MP CD4⁺ T lymphocytes as well as late activation of naïve cells, thereby contributing to maintenance of T cell homeostasis.

Keywords: CD4 T lymphocytes; homeostasis; inflammation; memory; regulatory T cells.

MeSH terms

Animals
CD4-Positive T-Lymphocytes / immunology
Cell Differentiation / immunology
Cell Proliferation
Immunologic Memory*
Lymphocyte Activation* / immunology
Memory T Cells / immunology
Memory T Cells / metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic*
Phenotype
Signal Transduction
T-Lymphocytes, Regulatory* / immunology
Th1 Cells / immunology

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Japan Society for the Promotion of Science, 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, TK 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. JL was supported by JST SPRING (Grant Number JPMJSP2114). This work was supported in part by the Division of Intramural Research of the NIAID, NIH.