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Using two disparate virus challenges of mice, we show that splenic CD8+ memory T cells rapidly produced IFN-\u03b3 in vivo; however, within 18\u201324 h, IFN-\u03b3 synthesis was terminated and remained undetectable for \u226548 h. A similar on\/off response was observed in CD8+ memory T cells in the peritoneal cavity. Cessation of IFN-\u03b3 production in vivo occurred despite the continued presence of immunostimulatory viral Ag, indicating that the initial IFN-\u03b3 response had been actively downregulated and that the cells had been rendered refractory to subsequent in vivo Ag contact. Downregulation of IFN-\u03b3 synthesis was accompanied by the upregulation of inhibitory receptor expression on the T cells, and ex vivo analyses using synthetic peptides revealed a concurrent hierarchical loss of cytokine responsiveness (IL-2, then TNF, then IFN-\u03b3) taking place during the first 24 h following Ag contact. Thus, within hours of virus challenge, CD8+ memory T cells display the standard hallmarks of T cell exhaustion, a phenotype that previously was associated only with chronic diseases and that is generally viewed as a gradually developing and pathological change in T cell function. Our data suggest that, instead, the \u201cexhaustion\u201d phenotype is a rapid and normal physiological T cell response.<\/jats:p>","DOI":"10.4049\/jimmunol.1300920","type":"journal-article","created":{"date-parts":[[2013,9,12]],"date-time":"2013-09-12T02:55:01Z","timestamp":1378954501000},"page":"4211-4222","source":"Crossref","is-referenced-by-count":19,"title":["CD8+ Memory T Cells Appear Exhausted within Hours of Acute Virus Infection"],"prefix":"10.1093","volume":"191","author":[{"given":"Martin P","family":"Hosking","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbial Science, The Scripps Research Institute , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia T","family":"Flynn","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Science, The Scripps Research Institute , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Botten","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Vermont College of Medicine , Burlington, VT 05405"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Lindsay","family":"Whitton","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Science, The Scripps Research Institute , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,10,15]]},"reference":[{"key":"2025032405474860000_r1","doi-asserted-by":"crossref","first-page":"2141","DOI":"10.1084\/jem.184.6.2141","article-title":"Resting memory CD8+ T cells are hyperreactive to antigenic challenge in vitro","volume":"184","author":"Pihlgren","year":"1996","journal-title":"J. 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