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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.<\/jats:p>","DOI":"10.1084\/jem.20220386","type":"journal-article","created":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T02:20:52Z","timestamp":1668478852000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":29,"title":["Construction of a T cell receptor signaling range for spontaneous development of autoimmune disease"],"prefix":"10.1084","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1660-9892","authenticated-orcid":true,"given":"Atsushi","family":"Tanaka","sequence":"first","affiliation":[{"name":"Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 1"},{"name":"Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan 2"},{"name":"Department of Frontier Research in Tumor Immunology, Center of 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