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• W4200568616 endingPage "160" @default.
• W4200568616 startingPage "145" @default.
• W4200568616 abstract "Establishing both central and peripheral tolerance requires the appropriate TCR signaling strength to discriminate self- from agonist-peptide bound to self MHC molecules. ZAP70, a cytoplasmic tyrosine kinase, directly interacts with the TCR complex and plays a central and requisite role in TCR signaling in both thymocytes and peripheral T cells. By studying ZAP70 hypomorphic mutations in mice and humans with a spectrum of hypoactive or hyperactive activities, we have gained insights into mechanisms of central and peripheral tolerance. Interestingly, both hypoactive and hyperactive ZAP70 can lead to the development of autoimmune diseases, albeit through distinct mechanisms. Immature thymocytes and mature T cells rely on normal ZAP70 function to complete their development in the thymus and to modulate T cell responses in the periphery. Hypoactive ZAP70 function compromises key developmental checkpoints required to establish central tolerance, allowing thymocytes with potentially self-reactive TCRs a greater chance to escape negative selection. Such 'forbidden clones' may escape into the periphery and may pose a greater risk for autoimmune disease development since they may not engage negative regulatory mechanisms as effectively. Hyperactive ZAP70 enhances thymic negative selection but some thymocytes will, nonetheless, escape negative selection and have greater sensitivity to weak and self-ligands. Such cells must be controlled by mechanisms involved in anergy, expansion of Tregs, and upregulation of inhibitory receptors or signaling molecules. However, such potentially autoreactive cells may still be able to escape control by peripheral negative regulatory constraints. Consistent with findings in Zap70 mutants, the signaling defects in at least one ZAP70 substrate, LAT, can also lead to autoimmune disease. By dissecting the similarities and differences among mouse models of patient disease or mutations in ZAP70 that affect TCR signaling strength, we have gained insights into how perturbed ZAP70 function can lead to autoimmunity. Because of our work and that of others on ZAP70, it is likely that perturbations in other molecules affecting TCR signaling strength will be identified that also overcome tolerance mechanisms and cause autoimmunity. Delineating these molecular pathways could lead to the development of much needed new therapeutic targets in these complex diseases." @default.
• W4200568616 created "2021-12-31" @default.
• W4200568616 creator A5002615738 @default.
• W4200568616 creator A5050836076 @default.
• W4200568616 creator A5056335660 @default.
• W4200568616 creator A5072643421 @default.
• W4200568616 creator A5076447792 @default.
• W4200568616 date "2021-12-18" @default.
• W4200568616 modified "2023-10-14" @default.
• W4200568616 title "ZAP70, too little, too much can lead to autoimmunity*" @default.
• W4200568616 cites W1513014113 @default.
• W4200568616 cites W1530890173 @default.
• W4200568616 cites W1559516752 @default.
• W4200568616 cites W1893566975 @default.
• W4200568616 cites W1958962606 @default.
• W4200568616 cites W1965159033 @default.
• W4200568616 cites W1965319674 @default.
• W4200568616 cites W1966621240 @default.
• W4200568616 cites W1967758178 @default.
• W4200568616 cites W1970802795 @default.
• W4200568616 cites W1976062745 @default.
• W4200568616 cites W1977058089 @default.
• W4200568616 cites W1982161183 @default.
• W4200568616 cites W1982865105 @default.
• W4200568616 cites W1985115748 @default.
• W4200568616 cites W1987460610 @default.
• W4200568616 cites W1987755713 @default.
• W4200568616 cites W1989488426 @default.
• W4200568616 cites W1992438206 @default.
• W4200568616 cites W1996651004 @default.
• W4200568616 cites W2000779612 @default.
• W4200568616 cites W2005525391 @default.
• W4200568616 cites W2005935110 @default.
• W4200568616 cites W2009792318 @default.
• W4200568616 cites W2013712650 @default.
• W4200568616 cites W2017104717 @default.
• W4200568616 cites W2017784211 @default.
• W4200568616 cites W2019670504 @default.
• W4200568616 cites W2022116029 @default.
• W4200568616 cites W2024748688 @default.
• W4200568616 cites W2030269101 @default.
• W4200568616 cites W2032546353 @default.
• W4200568616 cites W2035833176 @default.
• W4200568616 cites W2039096179 @default.
• W4200568616 cites W2041726757 @default.
• W4200568616 cites W2046421048 @default.
• W4200568616 cites W2046901206 @default.
• W4200568616 cites W2046957298 @default.
• W4200568616 cites W2055444005 @default.
• W4200568616 cites W2055736811 @default.
• W4200568616 cites W2057024012 @default.
• W4200568616 cites W2058924454 @default.
• W4200568616 cites W2059942477 @default.
• W4200568616 cites W2063529214 @default.
• W4200568616 cites W2064253793 @default.
• W4200568616 cites W2068982799 @default.
• W4200568616 cites W2073526321 @default.
• W4200568616 cites W2077518158 @default.
• W4200568616 cites W2081100902 @default.
• W4200568616 cites W2081703273 @default.
• W4200568616 cites W2086333701 @default.
• W4200568616 cites W2090490897 @default.
• W4200568616 cites W2094612112 @default.
• W4200568616 cites W2096613461 @default.
• W4200568616 cites W2099092516 @default.
• W4200568616 cites W2100646106 @default.
• W4200568616 cites W2103089470 @default.
• W4200568616 cites W2105562449 @default.
• W4200568616 cites W2106251488 @default.
• W4200568616 cites W2107951685 @default.
• W4200568616 cites W2109479443 @default.
• W4200568616 cites W2110421291 @default.
• W4200568616 cites W2114614133 @default.
• W4200568616 cites W2121509750 @default.
• W4200568616 cites W2121833986 @default.
• W4200568616 cites W2122722718 @default.
• W4200568616 cites W2122742816 @default.
• W4200568616 cites W2123415376 @default.
• W4200568616 cites W2124346088 @default.
• W4200568616 cites W2127605217 @default.
• W4200568616 cites W2129958256 @default.
• W4200568616 cites W2130506153 @default.
• W4200568616 cites W2131443741 @default.
• W4200568616 cites W2134866427 @default.
• W4200568616 cites W2137717947 @default.
• W4200568616 cites W2140073887 @default.
• W4200568616 cites W2146488955 @default.
• W4200568616 cites W2148226248 @default.
• W4200568616 cites W2149829681 @default.
• W4200568616 cites W2152877078 @default.
• W4200568616 cites W2157927836 @default.
• W4200568616 cites W2160841060 @default.
• W4200568616 cites W2161816553 @default.
• W4200568616 cites W2168587760 @default.
• W4200568616 cites W2257862647 @default.
• W4200568616 cites W2259033521 @default.
• W4200568616 cites W2324016918 @default.
• W4200568616 cites W2395845086 @default.

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