{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:09:47Z","timestamp":1785409787172,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,26]]},"group-title":"Immunology","reference-count":21,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/00rs6vg23","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/05sjnvv07","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01hwjc346","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/00y27w112","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/02f3xk561","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The interaction between the Major Histocompatibility Complex Class I (MHC-I) \u03b13 domain and CD8\u03b1 has classically been viewed as a positive coreceptor interaction that stabilizes TCR signaling during antigen recognition. However, its physiological function in mature peripheral CD8+ T cells in vivo remains incompletely understood. Here, we identify the MHC-I \u03b13 domain\u2013CD8\u03b1 interaction as a previously unrecognized inhibitory pathway that tonically restrains peripheral CD8+ T-cell activation and maintains T-cell tolerance in vivo. Antibody-mediated disruption of the MHC-I \u03b13 domain\u2013CD8\u03b1 interaction induced spontaneous activation of peripheral CD8+ T cells without impairing their survival, lowered the threshold for antigen-induced activation, and enhanced responsiveness to cognate peptide stimulation. In peptide-induced OT-I T-cell anergy models, blockade of either H-2D\n                  <jats:sup>b<\/jats:sup>\n                  or H-2K\n                  <jats:sup>b<\/jats:sup>\n                  \u03b13 domain interactions with CD8\u03b1 prevented the induction of anergy and restored responsiveness of previously anergic T cells. Notably, blockade of the H-2K\n                  <jats:sup>b<\/jats:sup>\n                  \u03b13 domain enhanced OT-I responses despite simultaneously disrupting the classical positive coreceptor interaction within the TCR\u2013peptide\u2013MHC complex, indicating that tonic inhibitory signaling mediated by the MHC-I \u03b13 domain predominates under these conditions. Together, these findings redefine the classical MHC-I\u2013CD8\u03b1 interaction as a bidirectional pathway that not only supports antigen recognition but also imposes tonic inhibitory control over peripheral CD8+ T cells. These results identify the MHC-I \u03b13 domain\u2013CD8\u03b1 axis as a potential target for reversing T-cell tolerance and enhancing antitumor or antiviral immunity.\n                <\/jats:p>","DOI":"10.64898\/2026.05.21.726907","type":"posted-content","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T16:55:15Z","timestamp":1779814515000},"source":"Crossref","is-referenced-by-count":0,"title":["The in vivo inhibitory function of the MHC-I \u03b13 domain\u2013CD8\u03b1 interaction"],"prefix":"10.64898","author":[{"given":"Juanjuan","family":"Zhao","sequence":"first","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center-James, Columbus, OH 43210, USA"},{"name":"Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center-James, Columbus, OH 43210, 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