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However, they undergo a swift decline under chronic antigen stimulation. In this study, we found that memory CD8 T cells\u2019 heightened activation sensitivity promotes terminal differentiation and impairs the formation of CXCR5+Tim-3\u2212 progenitor subsets, resulting in reduced persistence. This defect was commonly observed in memory CD8 T cells generated by diverse immunization strategies. Mechanistically, their inability to generate progenitor cells was not due to insufficient expression of TCF1 or TOX upregulation. Importantly, blockade of type I interferon signaling during priming restored progenitor differentiation of secondary activated CD8 T cells. These findings highlight that the activation context of memory CD8 T cells critically influences their fate during persistent infection and suggest that modulating inflammatory signals may enhance the durability of secondary responses.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag164","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:26:38Z","timestamp":1783556798000},"source":"Crossref","is-referenced-by-count":0,"title":["Differential stem-like potential of na\u00efve and memory CD8 T cells after chronic infection"],"prefix":"10.1093","volume":"215","author":[{"given":"Kyungmin","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Immunology, Sungkyunkwan University School of Medicine , Suwon,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junghwa","family":"Lee","sequence":"additional","affiliation":[{"name":"Viral Immunology Laboratory, Institut Pasteur Korea , Seongnam,","place":["Republic of Korea"]},{"name":"Emory Vaccine Center, Emory University School of Medicine , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9591-2621","authenticated-orcid":false,"given":"Rafi","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0223-1198","authenticated-orcid":false,"given":"Se Jin","family":"Im","sequence":"additional","affiliation":[{"name":"Department of Immunology, Sungkyunkwan University School of Medicine , Suwon,","place":["Republic of Korea"]},{"name":"Emory Vaccine Center, Emory University School of Medicine , Atlanta, GA,","place":["United 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