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This review summarizes current evidence on how CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell subsets shape the magnitude, breadth, and durability of immunity to SARS\u2010CoV\u20102 and influenza virus. mRNA vaccines elicit a potent Th1\/Tfh1\u2010biased response that generates high\u2010affinity neutralizing antibodies and cytotoxic CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells (CD4\u2010CTLs) with stem\u2010cell memory properties. However, this strong type I bias may come at the cost of long\u2010term maintenance of humoral memory. Natural infection additionally establishes tissue\u2010resident memory CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells (CD4 TRMs) at respiratory mucosal surfaces, providing a frontline defense that current intramuscular vaccines fail to recapitulate efficiently. Crucially, this T cell immunity proves far more resilient than neutralizing antibodies against Variants of Concern, as many memory T cell epitopes from the ancestral strain are conserved across successive variants, a robustness further reinforced by pre\u2010existing cross\u2010reactive CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells primed through prior seasonal coronavirus exposure or influenza infection. These observations argue for a fundamental shift in vaccine design toward mucosal delivery and conserved\u2010epitope antigens to achieve durable, broadly cross\u2010reactive protection.\n                  <\/jats:p>","DOI":"10.1111\/imr.70148","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T06:05:55Z","timestamp":1785305155000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of\n                    <scp>CD4<\/scp>\n                    T Cell Repertoire and Immune Memory Mechanisms in Vaccination and Infection Immunity"],"prefix":"10.1111","volume":"341","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7867-3086","authenticated-orcid":false,"given":"Masato","family":"Kubo","sequence":"first","affiliation":[{"name":"Immunomonitoring Center (KIC) Shogoin\u2010Kawahara\u2010cho Kyoto University  Kyoto Japan"},{"name":"Division of Molecular Pathology, Research Institute for Biomedical Science Tokyo University of Science  Noda\u2010shi Chiba Japan"},{"name":"Laboratory for Cytokine Regulation, Center for Integrative Medical Science (IMS) RIKEN Yokohama Institute  Yokohama Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04385-3"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05053-w"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2020.03.005"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-01122-w"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2119270"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)00017-4"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-030409-101212"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3152"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20150519"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.05.015"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2021.100204"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(21)00416-3"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.07.040189.001045"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3365"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8097338"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80702-3"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80240-8"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1966"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.07.035"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-031210-101400"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.11.001"},{"key":"e_1_2_14_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature20810"},{"key":"e_1_2_14_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.05.009"},{"key":"e_1_2_14_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1079490"},{"key":"e_1_2_14_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2523"},{"key":"e_1_2_14_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells13070639"},{"key":"e_1_2_14_28_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20021052"},{"key":"e_1_2_14_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2017.243"},{"key":"e_1_2_14_30_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abf7550"},{"key":"e_1_2_14_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03791-x"},{"key":"e_1_2_14_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2814-7"},{"key":"e_1_2_14_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01163-9"},{"key":"e_1_2_14_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3563"},{"key":"e_1_2_14_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2016.11.059"},{"key":"e_1_2_14_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.10.004"},{"key":"e_1_2_14_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31142-5"},{"key":"e_1_2_14_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03738-2"},{"key":"e_1_2_14_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.12.026"},{"key":"e_1_2_14_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.11.009"},{"key":"e_1_2_14_41_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abl5344"},{"key":"e_1_2_14_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110235"},{"key":"e_1_2_14_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1081047"},{"key":"e_1_2_14_44_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501118"},{"key":"e_1_2_14_45_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02123-15"},{"key":"e_1_2_14_46_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2118312119"},{"key":"e_1_2_14_47_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abl9105"},{"key":"e_1_2_14_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-01095-w"},{"key":"e_1_2_14_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00815-z"},{"key":"e_1_2_14_50_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.182615"},{"key":"e_1_2_14_51_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1002742"},{"key":"e_1_2_14_52_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201733"},{"key":"e_1_2_14_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2022.102278"},{"key":"e_1_2_14_54_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01069-10"},{"key":"e_1_2_14_55_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20251793"},{"key":"e_1_2_14_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23333-3"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