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Epitope mapping culminated in functional peptide\u2010based stimulation assays and tetramer staining, which together provide exquisite resolution of individual responses. Despite these tools, quantitative assessment of epitope\u2010resolved responses in complex human infections and tumors has rarely been applied at scale. As a result, no epitope\u2010aware correlates of protection or risk have been established for major infections, and most human T cell profiling still occurs at the level of representative epitopes or bulk assays. In this review, I propose that variation in specificity, defined as distinct epitope\u2010level responses across individuals, represents a largely untested critical element in our assessment of anti\u2010pathogen and antitumor immunity. Advances in TCR repertoire profiling and reverse epitope discovery now make formal tests of this hypothesis tractable, and I discuss approaches to determine the extent to which epitope variation underlies the noise and variation of human immune phenotypes.<\/jats:p>","DOI":"10.1111\/imr.70184","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T09:16:24Z","timestamp":1791364584000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Entering the Age of Specificity in T Cell Immunity"],"prefix":"10.1111","volume":"343","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7955-0256","authenticated-orcid":false,"given":"Paul G.","family":"Thomas","sequence":"first","affiliation":[{"name":"Program in Immunology and Vaccine Development, Vaccine and Infectious Disease Division Fred Hutchinson Cancer Center  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.03.037"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2020.101418"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/9710376"},{"issue":"12","key":"e_1_2_12_5_1","doi-asserted-by":"crossref","first-page":"7890","DOI":"10.4049\/jimmunol.178.12.7890","article-title":"A Quantitative Analysis of the Variables Affecting the Repertoire of T Cell Specificities Recognized After Vaccinia Virus Infection","volume":"178","author":"Assarsson E.","year":"2007","journal-title":"Journal of Immunology"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2021.100204"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41541\u2010023\u201000794\u20109"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines6030043"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpim.14"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/COH.0000000000000748"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.050567397"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1195271"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1204199109"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.54558"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2342"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070784"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081127"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.76.24.12584\u201012595.2002"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI36587"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2008.05.045"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.832206"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fviro.2023.1198361"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.143"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2024.10.006"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00251\u2010023\u201001293\u2010w"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/0198\u20108859(94)90079\u20105"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.35381"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3001012"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010022\u201005501\u20107"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kex517"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI9295"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40028"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20051357"},{"issue":"2","key":"e_1_2_12_34_1","doi-asserted-by":"crossref","first-page":"696","DOI":"10.4049\/jimmunol.174.2.696","article-title":"Vaccination With an Acidic Polymerase Epitope of Influenza Virus Elicits a Potent Antiviral T Cell Response but Delayed Clearance of an Influenza Virus Challenge","volume":"174","author":"Crowe S. 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