{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T17:32:05Z","timestamp":1792690325742,"version":"4.5.0"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T00:00:00Z","timestamp":1701993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["F30AI167482"],"award-info":[{"award-number":["F30AI167482"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Significant evidence suggests a connection between transplant rejection and the presence of high levels of pre-existing memory T cells. Viral infection can elicit viral-specific memory T cells that cross-react with allo-MHC capable of driving allograft rejection in mice. Despite these advances, and despite their critical role in transplant rejection, a systematic study of allo-reactive memory T cells, their specificities, and the role of cross-reactivity with viral antigens has not been performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we established a model to identify, isolate, and characterize cross-reactive T cells using Nur77 reporter mice (C57BL\/6 background), which transiently express GFP exclusively upon TCR engagement. We infected Nur77 mice with lymphocytic choriomeningitis virus (LCMV-Armstrong) to generate a robust memory compartment, where quiescent LCMV-specific memory CD8<jats:sup>+<\/jats:sup> T cells could be readily tracked with MHC tetramer staining. Then, we transplanted LCMV immune mice with allogeneic hearts and monitored expression of GFP within MHC-tetramer defined viral-specific T cells as an indicator of their ability to cross-react with alloantigens.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Strikingly, prior LCMV infection significantly increased the kinetics and magnitude of rejection as well as CD8<jats:sup>+<\/jats:sup> T cell recruitment into allogeneic, but not syngeneic, transplanted hearts, relative to non-infected controls. Interestingly, as early as day 1 after allogeneic heart transplant an average of ~8% of MHC-tetramer<jats:sup>+<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells expressed GFP, in contrast to syngeneic heart transplants, where the frequency of viral-specific CD8<jats:sup>+<\/jats:sup> T cells that were GFP<jats:sup>+<\/jats:sup> was &amp;lt;1%. These data show that a significant percentage of viral-specific memory CD8<jats:sup>+<\/jats:sup> T cells expressed T cell receptors that also recognized alloantigens <jats:italic>in vivo<\/jats:italic>. Notably, the frequency of cross-reactive CD8<jats:sup>+<\/jats:sup> T cells differed depending upon the viral epitope. Further, TCR sequences derived from cross-reactive T cells harbored distinctive motifs that may provide insight into cross-reactivity and allo-specificity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In sum, we have established a mouse model to track viral-specific, allo-specific, and cross-reactive T cells; revealing that prior infection elicits substantial numbers of viral-specific T cells that cross-react to alloantigen, respond very early after transplant, and may promote rapid rejection.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1287546","type":"journal-article","created":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T12:45:38Z","timestamp":1702039538000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Prior viral infection primes cross-reactive CD8+ T cells that respond to mouse heart allografts"],"prefix":"10.3389","volume":"14","author":[{"given":"M. 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