Self antigen-driven, undifferentiated memory-phenotype CD4 T lymphocytes can induce mild and systemic inflammation by differentiating into effector and regulatory T cells

Abstract In adaptive immune responses, naïve CD4 +T lymphocytes that have T cell receptors (TCRs) reactive to challenged foreign antigens are activated to differentiate into antigen-specific effector and memory cells. We have recently reported that in steady state, peripheral naïve precursors can also recognize self antigens to spontaneously acquire a memory phenotype (MP) and that such naturally arising “MP cells” can exert innate immune function in host defense. Given the self-reactivity of MP cells, it is likely that the same T lymphocyte population also has the capacity to induce autoimmune and/or inflammatory disease. Here we show that in lymphopenic environment, self antigen-driven MP cells can evoke mild and persistent inflammation in various organs including colon, lungs, kidneys, and liver. The MP cell-driven colitis is dependent on commensal microbiota as well as cytokines IFN-γ and IL-17A while inflammation in the other organs is independent of these factors. On the other hand, we demonstrate using combined single cell RNA sequencing, TCR sequencing, and flow cytometric approaches that MP as compared to naïve CD4 +T lymphocytes more efficiently differentiate into regulatory T (Treg) cells in a TGF-β-dependent fashion, thereby partially ameliorating inflammation. We further provide evidence arguing that these Th1, Th17, and Treg cells are generated from preexisting, undifferentiated T-bet −rather than T-bet +MP subset. Altogether, our results identify self-driven T-bet −MP cells as a multi-potent CD4 +T lymphocyte population that can induce systemic and mild inflammation by differentiating into Th1 and Th17 effector as well as Treg cells. This work was supported by the Japan Society for the Promotion of Science, Astellas Foundation for Research on Metabolic Disorders, Bristol-Myers Squibb, Cell Science Research Foundation, Chemo-Sero-Therapeutic Research Institute, Daiichi Sankyo Foundation of Life Science, GlaxoSmithKline, 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, Kanae Foundation for the Promotion of Medical Science, Kobayashi Foundation, Life Science Foundation of Japan, Mitsubishi Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, MSD Life Science 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. Akihisa Kawajiri was supported by the PhD Scholarship (Kibou Project) from Japanese Society for Immunology.