{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T15:09:04Z","timestamp":1761059344953,"version":"3.40.3"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2012,7,1]],"date-time":"2012-07-01T00:00:00Z","timestamp":1341100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>By the peak of the CD8+ T cell response, the effector cell pool consists of a heterogeneous population of cells that includes both those with an increased propensity to become long-lived memory cells (memory precursor effector cells; MPEC) and those that are terminally differentiated cells (short-lived effector cells; SLEC). Numerous studies have established the critical role that functional avidity plays in determining the in vivo efficacy of CD8+ effector cells. Currently, how functional avidity differs in MPEC versus SLEC and the evolution of this property within these two populations during the expansion and contraction of the response are unknown. The data presented in this study show that at the peak of the effector response generated after poxvirus infection, SLEC were of higher functional avidity than their MPEC counterpart. Over time, however, SLEC exhibited a decrease in peptide sensitivity. This is in contrast to MPEC, which showed a modest increase in peptide sensitivity as the response reached equilibrium. The decrease in functional avidity in SLEC was independent of CD8 modulation or the amount of Ag receptor expressed by the T cell. Instead, the loss in sensitivity was correlated with decreased expression and activation of ZAP70 and Lck, critical components of TCR membrane proximal signaling. These results highlight the potential contribution of avidity in the differentiation and evolution of the T cell effector response after viral infection.<\/jats:p>","DOI":"10.4049\/jimmunol.1102579","type":"journal-article","created":{"date-parts":[[2012,6,17]],"date-time":"2012-06-17T21:39:54Z","timestamp":1339969194000},"page":"638-645","source":"Crossref","is-referenced-by-count":8,"title":["Changes in Functional but Not Structural Avidity during Differentiation of CD8+ Effector Cells In Vivo after Virus Infection"],"prefix":"10.1093","volume":"189","author":[{"given":"Samuel","family":"Amoah","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Wake Forest University School of Medicine , Winston-Salem, NC 27157"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rama D","family":"Yammani","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Wake Forest University School of Medicine , Winston-Salem, NC 27157"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason M","family":"Grayson","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Wake Forest University School of Medicine , Winston-Salem, NC 27157"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martha A","family":"Alexander-Miller","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Wake Forest University School of Medicine , Winston-Salem, NC 27157"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2012,7,15]]},"reference":[{"key":"2025032409211526600_r1","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.immuni.2007.07.010","article-title":"Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor","volume":"27","author":"Joshi","year":"2007","journal-title":"Immunity"},{"key":"2025032409211526600_r2","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1038\/ni1009","article-title":"Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells","volume":"4","author":"Kaech","year":"2003","journal-title":"Nat. Immunol."},{"key":"2025032409211526600_r3","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1111\/j.1600-065X.2010.00926.x","article-title":"Generation of effector CD8+ T cells and their conversion to memory T cells","volume":"236","author":"Cui","year":"2010","journal-title":"Immunol. Rev."},{"key":"2025032409211526600_r4","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1073\/pnas.0909945107","article-title":"CD4+ T cell regulation of CD25 expression controls development of short-lived effector CD8+ T cells in primary and secondary responses","volume":"107","author":"Obar","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032409211526600_r5","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.immuni.2009.11.010","article-title":"Prolonged interleukin-2Ralpha expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo","volume":"32","author":"Kalia","year":"2010","journal-title":"Immunity"},{"key":"2025032409211526600_r6","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.immuni.2009.11.012","article-title":"Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells","volume":"32","author":"Pipkin","year":"2010","journal-title":"Immunity"},{"key":"2025032409211526600_r7","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/nri2274","article-title":"T-cell quality in memory and protection: implications for vaccine design","volume":"8","author":"Seder","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"2025032409211526600_r8","doi-asserted-by":"crossref","first-page":"4102","DOI":"10.1073\/pnas.93.9.4102","article-title":"Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy","volume":"93","author":"Alexander-Miller","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032409211526600_r9","doi-asserted-by":"crossref","first-page":"989","DOI":"10.4049\/jimmunol.162.2.989","article-title":"High avidity CTLs for two self-antigens demonstrate superior in vitro and in vivo antitumor efficacy","volume":"162","author":"Zeh","year":"1999","journal-title":"J. Immunol."},{"key":"2025032409211526600_r10","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.4049\/jimmunol.162.4.2227","article-title":"Isolation of high avidity melanoma-reactive CTL from heterogeneous populations using peptide-MHC tetramers","volume":"162","author":"Yee","year":"1999","journal-title":"J. Immunol."},{"key":"2025032409211526600_r11","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1084\/jem.187.10.1647-b","article-title":"Protective immunity does not correlate with the hierarchy of virus-specific cytotoxic T cell responses to naturally processed peptides","volume":"187","author":"Gallimore","year":"1998","journal-title":"J. Exp. Med."},{"key":"2025032409211526600_r12","doi-asserted-by":"crossref","first-page":"5769","DOI":"10.1128\/JVI.74.13.5769-5775.2000","article-title":"In vivo induction of a high-avidity, high-frequency cytotoxic T-lymphocyte response is associated with antiviral protective immunity","volume":"74","author":"Sedlik","year":"2000","journal-title":"J. Virol."},{"key":"2025032409211526600_r13","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1002\/hep.22379","article-title":"Selection of high-avidity CD8 T cells correlates with control of hepatitis C virus infection","volume":"48","author":"Neveu","year":"2008","journal-title":"Hepatology"},{"key":"2025032409211526600_r14","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1084\/jem.20070784","article-title":"Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover","volume":"204","author":"Almeida","year":"2007","journal-title":"J. Exp. Med."},{"key":"2025032409211526600_r15","doi-asserted-by":"crossref","first-page":"6351","DOI":"10.1182\/blood-2009-02-206557","article-title":"Antigen sensitivity is a major determinant of CD8+ T-cell polyfunctionality and HIV-suppressive activity","volume":"113","author":"Almeida","year":"2009","journal-title":"Blood"},{"key":"2025032409211526600_r16","doi-asserted-by":"crossref","first-page":"5723","DOI":"10.4049\/jimmunol.0900069","article-title":"The avidity and lytic efficiency of the CTL response to HTLV-1","volume":"182","author":"Kattan","year":"2009","journal-title":"J. Immunol."},{"key":"2025032409211526600_r17","doi-asserted-by":"crossref","first-page":"5824","DOI":"10.4049\/jimmunol.167.10.5824","article-title":"Manipulation of avidity to improve effectiveness of adoptively transferred CD8(+) T cells for melanoma immunotherapy in human MHC class I-transgenic mice","volume":"167","author":"Bullock","year":"2001","journal-title":"J. Immunol."},{"key":"2025032409211526600_r18","doi-asserted-by":"crossref","first-page":"972","DOI":"10.4049\/jimmunol.149.3.972","article-title":"Discrepancy between in vitro measurable and in vivo virus neutralizing cytotoxic T cell reactivities. Low T cell receptor specificity and avidity sufficient for in vitro proliferation or cytotoxicity to peptide-coated target cells but not for in vivo protection","volume":"149","author":"Speiser","year":"1992","journal-title":"J. Immunol."},{"key":"2025032409211526600_r19","doi-asserted-by":"crossref","first-page":"14736","DOI":"10.1073\/pnas.93.25.14736","article-title":"Transfected Drosophila cells as a probe for defining the minimal requirements for stimulating unprimed CD8+ T cells","volume":"93","author":"Cai","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032409211526600_r20","doi-asserted-by":"crossref","first-page":"2929","DOI":"10.1002\/eji.200526330","article-title":"Help signals provided by lymphokines modulate the activation and apoptotic programs induced by partially agonistic peptides in specific cytotoxic T lymphocytes","volume":"35","author":"Uhlin","year":"2005","journal-title":"Eur. J. Immunol."},{"key":"2025032409211526600_r21","doi-asserted-by":"crossref","first-page":"3256","DOI":"10.4049\/jimmunol.1001362","article-title":"SHP-1 in T cells limits the production of CD8 effector cells without impacting the formation of long-lived central memory cells","volume":"185","author":"Fowler","year":"2010","journal-title":"J. Immunol."},{"key":"2025032409211526600_r22","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1128\/jvi.67.1.348-352.1993","article-title":"A \u201cstring-of-beads\u201d vaccine, comprising linked minigenes, confers protection from lethal-dose virus challenge","volume":"67","author":"Whitton","year":"1993","journal-title":"J. Virol."},{"key":"2025032409211526600_r23","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.immuni.2007.10.012","article-title":"A single naive CD8+ T cell precursor can develop into diverse effector and memory subsets","volume":"27","author":"Stemberger","year":"2007","journal-title":"Immunity"},{"key":"2025032409211526600_r24","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1189\/jlb.0809575","article-title":"Pivotal Advance: nonfunctional lung effectors exhibit decreased calcium mobilization associated with reduced expression of ORAI1","volume":"87","author":"Arimilli","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"2025032409211526600_r25","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1128\/JVI.79.6.3339-3349.2005","article-title":"Altered function in CD8+ T cells following paramyxovirus infection of the respiratory tract","volume":"79","author":"Gray","year":"2005","journal-title":"J. Virol."},{"key":"2025032409211526600_r26","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/nm0102-54","article-title":"Respiratory syncytial virus infection suppresses lung CD8+ T-cell effector activity and peripheral CD8+ T-cell memory in the respiratory tract","volume":"8","author":"Chang","year":"2002","journal-title":"Nat. Med."},{"key":"2025032409211526600_r27","doi-asserted-by":"crossref","first-page":"7799","DOI":"10.1128\/JVI.00840-08","article-title":"Regulation of cytokine production by virus-specific CD8 T cells in the lungs","volume":"82","author":"Fulton","year":"2008","journal-title":"J. Virol."},{"key":"2025032409211526600_r28","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.4049\/jimmunol.149.5.1613","article-title":"Beta-chain broadens range of CD8 recognition for MHC class I molecule","volume":"149","author":"Karaki","year":"1992","journal-title":"J. Immunol."},{"key":"2025032409211526600_r29","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.4049\/jimmunol.167.5.2577","article-title":"Peptide requirement for CTL activation reflects the sensitivity to CD3 engagement: correlation with CD8alphabeta versus CD8alphaalpha expression","volume":"167","author":"Cawthon","year":"2001","journal-title":"J. Immunol."},{"key":"2025032409211526600_r30","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/j.1365-2567.2007.02622.x","article-title":"Dose-dependent modulation of CD8 and functional avidity as a result of peptide encounter","volume":"122","author":"Kroger","year":"2007","journal-title":"Immunology"},{"key":"2025032409211526600_r31","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1038\/ni1268","article-title":"Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin","volume":"6","author":"Intlekofer","year":"2005","journal-title":"Nat. Immunol."},{"key":"2025032409211526600_r32","doi-asserted-by":"crossref","first-page":"7515","DOI":"10.4049\/jimmunol.177.11.7515","article-title":"Cutting Edge: IL-12 inversely regulates T-bet and eomesodermin expression during pathogen-induced CD8+ T cell differentiation","volume":"177","author":"Takemoto","year":"2006","journal-title":"J. Immunol."},{"key":"2025032409211526600_r33","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.immuni.2007.08.007","article-title":"Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection","volume":"27","author":"Kaech","year":"2007","journal-title":"Immunity"},{"key":"2025032409211526600_r34","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.immuni.2009.06.021","article-title":"Blimp-1 transcription factor is required for the differentiation of effector CD8(+) T cells and memory responses","volume":"31","author":"Kallies","year":"2009","journal-title":"Immunity"},{"key":"2025032409211526600_r35","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1093\/intimm\/dxq053","article-title":"Early events governing memory CD8+ T-cell differentiation","volume":"22","author":"Obar","year":"2010","journal-title":"Int. Immunol."},{"key":"2025032409211526600_r36","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1002\/eji.201040625","article-title":"Memory precursor phenotype of CD8+ T cells reflects early antigenic experience rather than memory numbers in a model of localized acute influenza infection","volume":"41","author":"Croom","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"2025032409211526600_r37","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1084\/jem.20071641","article-title":"Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates","volume":"205","author":"Sarkar","year":"2008","journal-title":"J. Exp. Med."},{"key":"2025032409211526600_r38","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.cellimm.2004.03.001","article-title":"High avidity CD8+ T cells generated from CD28-deficient or wildtype mice exhibit a differential dependence on lipid raft integrity for activation","volume":"227","author":"Cawthon","year":"2004","journal-title":"Cell. Immunol."},{"key":"2025032409211526600_r39","doi-asserted-by":"crossref","first-page":"7009","DOI":"10.4049\/jimmunol.166.12.7009","article-title":"Cutting edge: lipid raft integrity affects the efficiency of MHC class I tetramer binding and cell surface TCR arrangement on CD8+ T cells","volume":"166","author":"Drake","year":"2001","journal-title":"J. Immunol."},{"key":"2025032409211526600_r40","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/S1074-7613(00)80577-4","article-title":"Membrane compartmentation is required for efficient T cell activation","volume":"8","author":"Xavier","year":"1998","journal-title":"Immunity"},{"key":"2025032409211526600_r41","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1034\/j.1600-065X.2003.00001.x","article-title":"The roles of membrane microdomains (rafts) in T cell activation","volume":"191","author":"Horejs\u00ed","year":"2003","journal-title":"Immunol. Rev."},{"key":"2025032409211526600_r42","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/90650","article-title":"Functional avidity maturation of CD8(+) T cells without selection of higher affinity TCR","volume":"2","author":"Slifka","year":"2001","journal-title":"Nat. Immunol."},{"key":"2025032409211526600_r43","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.virol.2009.05.021","article-title":"CD8+ T cell immunodominance shifts during the early stages of acute LCMV infection independently from functional avidity maturation","volume":"390","author":"Rau\u00e9","year":"2009","journal-title":"Virology"},{"key":"2025032409211526600_r44","doi-asserted-by":"crossref","first-page":"174","DOI":"10.4049\/jimmunol.170.1.174","article-title":"High avidity CD8+ T cells are the initial population elicited following viral infection of the respiratory tract","volume":"170","author":"Gray","year":"2003","journal-title":"J. Immunol."},{"key":"2025032409211526600_r45","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1128\/JVI.02229-09","article-title":"Two kinetic patterns of epitope-specific CD8 T-cell responses following murine gammaherpesvirus 68 infection","volume":"84","author":"Freeman","year":"2010","journal-title":"J. Virol."},{"key":"2025032409211526600_r46","doi-asserted-by":"crossref","first-page":"748","DOI":"10.4049\/jimmunol.179.2.748","article-title":"Cutting edge: CD8+ T cell clones possess the potential to differentiate into both high- and low-avidity effector cells","volume":"179","author":"Kroger","year":"2007","journal-title":"J. Immunol."},{"key":"2025032409211526600_r47","doi-asserted-by":"crossref","first-page":"3492","DOI":"10.4049\/jimmunol.169.7.3492","article-title":"Optimal colocalization of TCR and CD8 as a novel mechanism for the control of functional avidity","volume":"169","author":"Cawthon","year":"2002","journal-title":"J. Immunol."},{"key":"2025032409211526600_r48","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1002\/eji.200324196","article-title":"Proximal changes in signal transduction that modify CD8+ T cell responsiveness in vivo","volume":"33","author":"Guillaume","year":"2003","journal-title":"Eur. J. Immunol."},{"key":"2025032409211526600_r49","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/S0198-8859(02)00455-X","article-title":"P59(fyn) is upregulated in anergic CD8+ T cells","volume":"63","author":"Welke","year":"2002","journal-title":"Hum. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/189\/2\/638\/62481644\/1102579.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/189\/2\/638\/62481644\/1102579.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T04:24:12Z","timestamp":1743049452000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/189\/2\/638\/7989850"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,7]]},"references-count":49,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2012,7,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1102579","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"type":"print","value":"0022-1767"},{"type":"electronic","value":"1550-6606"}],"subject":[],"published-other":{"date-parts":[[2012,7]]},"published":{"date-parts":[[2012,7]]}}}