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It has been postulated that maintaining them requires help from CD4 T cells, because adoptively transferred memory CD8 T cells persist poorly in MHC class II (MHCII)-deficient mice. Here we show that chronic interferon-\u03b3 signals, not CD4 T cell-deficiency, are responsible for their attrition in MHCII-deficient environments. Excess IFN-\u03b3 is produced primarily by endogenous colonic CD8 T cells in MHCII-deficient mice. IFN-\u03b3 neutralization restores the number of memory CD8 T cells in MHCII-deficient mice, whereas repeated IFN-\u03b3 administration or transduction of a gain-of-function STAT1 mutant reduces their number in wild-type mice. CD127<jats:sup>high<\/jats:sup> memory cells proliferate actively in response to IFN-\u03b3 signals, but are more susceptible to attrition than CD127<jats:sup>low<\/jats:sup> terminally differentiated effector memory cells. Furthermore, single-cell RNA-sequencing of memory CD8 T cells reveals proliferating cells that resemble short-lived, terminal effector cells and documents global downregulation of gene signatures of long-lived memory cells in MHCII-deficient environments. We propose that chronic IFN-\u03b3 signals deplete memory CD8 T cells by compromising their long-term survival and by diverting self-renewing CD127<jats:sup>high<\/jats:sup> cells toward terminal differentiation.<\/jats:p>","DOI":"10.1038\/s41467-024-48704-4","type":"journal-article","created":{"date-parts":[[2024,5,28]],"date-time":"2024-05-28T10:01:49Z","timestamp":1716890509000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Memory CD8 T cells are vulnerable to chronic IFN-\u03b3 signals but not to CD4 T cell deficiency in MHCII-deficient mice"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3105-1547","authenticated-orcid":false,"given":"Ruka","family":"Setoguchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Sengiku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Kono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9955-4342","authenticated-orcid":false,"given":"Eiryo","family":"Kawakami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7867-3086","authenticated-orcid":false,"given":"Masato","family":"Kubo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5938-9378","authenticated-orcid":false,"given":"Tadashi","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8770-4593","authenticated-orcid":false,"given":"Shohei","family":"Hori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,28]]},"reference":[{"key":"48704_CR1","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1038\/ni1009","volume":"4","author":"SM Kaech","year":"2003","unstructured":"Kaech, S. 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