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Marriott Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015138","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>T cells have been shown to maintain a lower percentage (heteroplasmy) of the pathogenic m.3243A&gt;G variant (<jats:italic>MT\u2010TL1<\/jats:italic>, associated with maternally inherited diabetes and deafness [MIDD] and mitochondrial encephalomyopathy with lactic acidosis and stroke\u2010like episodes [MELAS]). The mechanism(s) underlying this purifying selection, however, remain unknown. Here we report that purified patient memory CD4+ T cells have lower bulk m.3243A&gt;G heteroplasmy compared to na\u00efve CD4+ T cells. In vitro activation of na\u00efve CD4+ m.3243A&gt;G patient T cells results in lower bulk m.3243A&gt;G heteroplasmy after proliferation. Finally, m.3243A&gt;G patient T cell receptor repertoire sequencing reveals relative oligoclonality compared to controls. These data support a role for T cell activation in peripheral, purifying selection against high m.3243A&gt;G heteroplasmy T cells at the level of the cell, in a likely cell\u2010autonomous fashion.<\/jats:p>","DOI":"10.1002\/jimd.12726","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T02:49:41Z","timestamp":1710816581000},"page":"757-765","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["T cell activation contributes to purifying selection against the MELAS\u2010associated m.3243A&gt;G pathogenic variant in blood"],"prefix":"10.1002","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7423-9538","authenticated-orcid":false,"given":"Melissa A.","family":"Walker","sequence":"first","affiliation":[{"name":"Department of Neurology Massachusetts General Hospital  Boston Massachusetts USA"},{"name":"Howard Hughes Medical Institute and the Department of Molecular Biology 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