{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T18:47:55Z","timestamp":1782154075759,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,19]]},"group-title":"Immunology","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["NIH R01\/56 AI109842"],"award-info":[{"award-number":["NIH R01\/56 AI109842"]}]},{"name":"NIH","award":["NIH R01AIO40127"],"award-info":[{"award-number":["NIH R01AIO40127"]}]},{"name":"CRI","award":["CRI4681"],"award-info":[{"award-number":["CRI4681"]}]},{"name":"SIG","award":["S10RR027366"],"award-info":[{"award-number":["S10RR027366"]}]},{"name":"SIG","award":["S10OD025052"],"award-info":[{"award-number":["S10OD025052"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Two prominent mechanisms by which tumors fend off immune control are by constraining the ability of T cells and CAR T cells to survive and expand in the tumor, and by restraining their ability to sustain full cytotoxic capacity. We identified I\u03baB\u03b4, encoded by\n                  <jats:italic>Nfkbid<\/jats:italic>\n                  , a poorly characterized I\u03baB family member, as a molecular lever that overcomes both of these constraints on anti-tumor CD8\n                  <jats:sup>+<\/jats:sup>\n                  tumor-infiltrating lymphocytes (TILs).\n                  <jats:italic>Nfkbid<\/jats:italic>\n                  is an NFAT target gene that is expressed in CD8\n                  <jats:sup>+<\/jats:sup>\n                  effector T cells and, at modest levels, in CD8\n                  <jats:sup>+<\/jats:sup>\n                  TILs. We found that\n                  <jats:italic>Nfkbid<\/jats:italic>\n                  depletion impaired TIL accumulation, exacerbating the growth of solid tumors. On the other hand, ectopic I\u03baB\u03b4 overexpression enhanced TIL expansion, reduced the expression of exhaustion-associated transcription factors and inhibitory receptors, and elevated cytotoxic molecule production, leading to enhanced tumor control. I\u03baB\u03b4 has a shorter protein isoform that is identical in a core region spanning the ankyrin-repeat domain known to interact with NF\u03baB proteins, but that lacks the \u223c150-residue N-terminal region. We showed that the shared core region is sufficient to drive T cell accumulation, whereas the N-terminal peptide region is required for robust effector function and to counter exhaustion, underscoring that tumor-infiltrating CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell accumulation and effector differentiation are separable programs. Our current study provides evidence that I\u03baB\u03b4, an atypical member of the NF\u03baB family, is a lever to overcome two cardinal deficits that limit CD8\n                  <jats:sup>+<\/jats:sup>\n                  TIL anti-tumor efficacy: impaired accumulation in the tumor and diminished effector function.\n                <\/jats:p>","DOI":"10.64898\/2026.06.17.732005","type":"posted-content","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T22:00:12Z","timestamp":1781906412000},"source":"Crossref","is-referenced-by-count":0,"title":["The atypical I\u03baB factor I\u03baB\u03b4 enhances CD8 T cell accumulation and effector functions in solid tumors"],"prefix":"10.64898","author":[{"given":"Barsha","family":"Dash","sequence":"first","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, 9420 Athena Circle, La Jolla, CA, 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaocui","family":"He","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, 9420 Athena Circle, La Jolla, CA, 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arlet","family":"Lara-Custodio","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, 9420 Athena Circle, La Jolla, CA, 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo J","family":"Arteaga-Vazquez","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, 9420 Athena Circle, La Jolla, CA, 92037, USA"},{"name":"School of Biological Sciences, University of California, San Diego"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhao","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, 9420 Athena Circle, La Jolla, CA, 92037, USA"},{"name":"School of Biological Sciences, University of California, San Diego"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Drum","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, 9420 Athena Circle, La Jolla, CA, 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, 9420 Athena Circle, La Jolla, CA, 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Johnson","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, 9420 Athena Circle, La Jolla, CA, 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuntian","family":"Zhu","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, 9420 Athena Circle, La Jolla, CA, 92037, USA"},{"name":"School of Biological Sciences, University of California, San Diego"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, 9420 Athena Circle, La Jolla, CA, 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srikanth","family":"Battu","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, 9420 Athena Circle, La Jolla, CA, 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edah\u00ed","family":"Gonz\u00e1lez-Avalos","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, 9420 Athena Circle, La Jolla, CA, 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjana","family":"Rao","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, 9420 Athena Circle, La Jolla, CA, 92037, USA"},{"name":"Department of Pharmacology, University of California, San Diego; 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