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We used mouse models and human transplant registry data to reveal that pregnancy induced exhausted CD8 T cells (Preg-TEX), which associated with prolonged allograft survival. Maternal CD8 T cells shared features of exhaustion with CD8 T cells from cancer and chronic infection, including transcriptional down-regulation of ribosomal proteins and up-regulation of TOX and inhibitory receptors. Similar to other models of T cell exhaustion, NFAT-dependent elements of the exhaustion program were induced by fetal antigen in pregnancy, whereas NFAT-independent elements did not require fetal antigen. Despite using conserved molecular circuitry, Preg-TEX cells differed from TEX cells in chronic viral infection with respect to magnitude and dependency of T cell hypofunction on NFAT-independent signals. Altogether, these data reveal the molecular mechanisms and clinical consequences of maternal CD8 T cell hypofunction and identify pregnancy as a previously unappreciated context in which T cell exhaustion may occur.<\/jats:p>","DOI":"10.1084\/jem.20201599","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T14:46:06Z","timestamp":1639061166000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":29,"title":["NFAT-dependent and -independent exhaustion circuits program maternal CD8 T cell hypofunction in pregnancy"],"prefix":"10.1084","volume":"219","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2572-1002","authenticated-orcid":true,"given":"Emma L.","family":"Lewis","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Pennsylvania, Philadelphia, PA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8571-3218","authenticated-orcid":true,"given":"Rong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Surgery, The University of Pennsylvania, Philadelphia, PA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6363-3572","authenticated-orcid":true,"given":"Jean-Christophe","family":"Beltra","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics, The University of Pennsylvania, Philadelphia, PA 3"},{"name":"Institute for Immunology, University of Pennsylvania, Philadelphia, PA 4"},{"name":"Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5738-2834","authenticated-orcid":true,"given":"Shin Foong","family":"Ngiow","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics, The University of Pennsylvania, Philadelphia, PA 3"},{"name":"Institute for Immunology, University of Pennsylvania, Philadelphia, PA 4"},{"name":"Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4649-079X","authenticated-orcid":true,"given":"Jordana","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Pennsylvania, Philadelphia, PA 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6368-8223","authenticated-orcid":true,"given":"Rahul","family":"Telange","sequence":"additional","affiliation":[{"name":"Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL 7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1930-279X","authenticated-orcid":true,"given":"Alexander","family":"Crane","sequence":"additional","affiliation":[{"name":"Department of Surgery, The University of Pennsylvania, Philadelphia, PA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7903-8295","authenticated-orcid":true,"given":"Deirdre","family":"Sawinski","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Pennsylvania, Philadelphia, PA 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0477-1956","authenticated-orcid":true,"given":"E. 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