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Memory CD8 T cells can be further subdivided into central memory, effector memory (TEM), and tissue-resident memory (TRM) subsets, which cooperate to confer immunological protection. Using mixed bone marrow chimeras and adoptive transfer studies in which CD8 T cells either do or do not express IL-21R, we discovered that under homeostatic or lymphopenic conditions IL-21 acts directly on CD8 T cells to favor the accumulation of TE\/TEM populations. The inability to perceive IL-21 signals under competitive conditions also resulted in lower levels of TRM phenotype cells and reduced expression of granzyme B in the small intestine. IL-21 differentially promoted the expression of the chemokine receptor CX3CR1 and the integrin \u03b14\u03b27 on CD8 T cells primed in vitro and on circulating CD8 T cells in the mixed bone marrow chimeras. The requirement for IL-21 to establish CD8 TE\/TEM and TRM subsets was overcome by acute lymphocytic choriomeningitis virus infection; nevertheless, memory virus-specific CD8 T cells remained dependent on IL-21 for optimal accumulation in lymphopenic environments. Overall, this study reveals a context-dependent role for IL-21 in sustaining effector phenotype CD8 T cells and influencing their migratory properties, accumulation, and functions.<\/jats:p>","DOI":"10.4049\/jimmunol.1401236","type":"journal-article","created":{"date-parts":[[2016,1,30]],"date-time":"2016-01-30T03:33:53Z","timestamp":1454124833000},"page":"2153-2166","source":"Crossref","is-referenced-by-count":47,"title":["A Context-Dependent Role for IL-21 in Modulating the Differentiation, Distribution, and Abundance of Effector and Memory CD8 T Cell Subsets"],"prefix":"10.1093","volume":"196","author":[{"given":"Yuan","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Microbiology, University of Alabama , Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen A","family":"Cox","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Alabama , Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon M","family":"Kahan","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Alabama , Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer T","family":"Ingram","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Alabama , Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2120-6625","authenticated-orcid":false,"given":"Rakesh K","family":"Bakshi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Alabama , Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan J","family":"Zajac","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Alabama , Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,3,1]]},"reference":[{"key":"2025030702141970600_r1","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.virol.2012.09.012","article-title":"Anti-viral CD8 T cells and the cytokines that they love","volume":"435","author":"Cox","year":"2013","journal-title":"Virology"},{"key":"2025030702141970600_r2","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/j.micinf.2010.08.008","article-title":"Interleukin-21: a multifunctional regulator of immunity to infections","volume":"12","author":"Yi","year":"2010","journal-title":"Microbes Infect."},{"key":"2025030702141970600_r3","doi-asserted-by":"crossref","first-page":"68","DOI":"10.4049\/jimmunol.173.1.68","article-title":"T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1\/Th2 effector cells that provide help for B cells","volume":"173","author":"Chtanova","year":"2004","journal-title":"J. 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