{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:40:58Z","timestamp":1790628058002,"version":"4.1.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T00:00:00Z","timestamp":1712534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Exhausted CD8 T cells (T<jats:sub>EX<\/jats:sub>) are associated with worse outcome in cancer yet better outcome in autoimmunity. Building on our past findings of increased TIGIT<jats:sup>+<\/jats:sup>KLRG1<jats:sup>+<\/jats:sup> T<jats:sub>EX<\/jats:sub> with teplizumab therapy in type 1 diabetes (T1D), in the absence of treatment we found that the frequency of TIGIT<jats:sup>+<\/jats:sup>KLRG1<jats:sup>+<\/jats:sup> T<jats:sub>EX<\/jats:sub> is stable within an individual but differs across individuals in both T1D and healthy control (HC) cohorts. This TIGIT<jats:sup>+<\/jats:sup>KLRG1<jats:sup>+<\/jats:sup> CD8 T<jats:sub>EX<\/jats:sub> population shares an exhaustion-associated EOMES gene signature in HC, T1D, rheumatoid arthritis (RA), and cancer subjects, expresses multiple inhibitory receptors, and is hyporesponsive <jats:italic>in vitro<\/jats:italic>, together suggesting co-expression of TIGIT and KLRG1 may broadly define human peripheral exhausted cells. In HC and RA subjects, lower levels of EOMES transcriptional modules and frequency of TIGIT<jats:sup>+<\/jats:sup>KLRG1<jats:sup>+<\/jats:sup> T<jats:sub>EX<\/jats:sub> were associated with RA HLA risk alleles (DR0401, 0404, 0405, 0408, 1001) even when considering disease status and cytomegalovirus (CMV) seropositivity. Moreover, the frequency of TIGIT<jats:sup>+<\/jats:sup>KLRG1<jats:sup>+<\/jats:sup> T<jats:sub>EX<\/jats:sub> was significantly increased in RA HLA risk but not non-risk subjects treated with abatacept (CTLA4Ig). The DR4 association and selective modulation with abatacept suggests that therapeutic modulation of T<jats:sub>EX<\/jats:sub> may be more effective in DR4 subjects and T<jats:sub>EX<\/jats:sub> may be indirectly influenced by cellular interactions that are blocked by abatacept.<\/jats:p>","DOI":"10.3389\/fimmu.2024.1383110","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T04:50:41Z","timestamp":1712551841000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Abatacept increases T cell exhaustion in early RA individuals who carry HLA risk alleles"],"prefix":"10.3389","volume":"15","author":[{"given":"Sarah Alice","family":"Long","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia S.","family":"Muir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britta 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