| Autor: |
Tanaka, Atsushi, Maeda, Shinji, Nomura, Takashi, Llamas-Covarrubias, Mara Anais, Tanaka, Satoshi, Jin, Lin, Lim, Ee Lyn, Morikawa, Hiromasa, Kitagawa, Yohko, Akizuki, Shuji, Ito, Yoshinaga, Fujimori, Chihiro, Hirota, Keiji, Murase, Tosei, Hashimoto, Motomu, Higo, Junichi, Zamoyska, Rose, Ueda, Ryuzo, Standley, Daron M., Sakaguchi, Noriko, Sakaguchi, Shimon |
| Zdroj: |
The Journal of Experimental Medicine; February 2023, Vol. 220 Issue: 2 pe20220386-e20220386, 1p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
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