Thymic selection and peripheral activation of conventional T (Tconv) and regulatory T (Treg) cells depend on TCR signaling, whose anomalies are causative of autoimmunity. Here, we expressed in normal mice mutated ZAP-70 molecules with different affinities for the CD3 chains, or wild type ZAP-70 at graded expression levels under tetracycline-inducible control. Both manipulations reduced TCR signaling intensity to various extents and thereby rendered those normally deleted self-reactive thymocytes to become positively selected and form a highly autoimmune TCR repertoire. The signal reduction more profoundly affected Treg development and function because their TCR signaling was further attenuated by Foxp3 that physiologically repressed the expression of TCR-proximal signaling molecules, including ZAP-70, upon TCR stimulation. Consequently, the TCR signaling intensity reduced to a critical range generated pathogenic autoimmune Tconv cells and concurrently impaired Treg development/function, leading to spontaneous occurrence of autoimmune/inflammatory diseases, such as autoimmune arthritis and inflammatory bowel disease. These results provide a general model of how altered TCR signaling evokes autoimmune disease.
Author Info: (1) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, WPI Immunology Frontier Re
Author Info: (1) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. Department of Frontier Research in Tumor Immunology, Center of Medical Innovation and Translational Research, Graduate School of Medicine, Osaka University, Osaka, Japan. (2) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. (3) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. (4) Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. Institute of Research in Biomedical Sciences, University Center of Health Sciences, University of Guadalajara, Guadalajara, Mexico. (5) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. (6) Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (7) Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (8) Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (9) Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (10) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. (11) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. (12) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. (13) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (14) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (15) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. (16) Institute for Protein Research, Osaka University, Suita, Japan. (17) Institute for Immunology and Infection Research, The University of Edinburgh, Edinburgh, UK. (18) Department of Tumor Immunology, Aichi Medical University School of Medicine, Aichi, Japan. (19) Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (20) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (21) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan.
