{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:58:24Z","timestamp":1785437904254,"version":"3.56.0"},"posted":{"date-parts":[[2026,1,13]]},"group-title":"Immunology","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01HL153162"],"award-info":[{"award-number":["R01HL153162"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01HL152078"],"award-info":[{"award-number":["R01HL152078"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R21AI185410"],"award-info":[{"award-number":["R21AI185410"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  During\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  (\n                  <jats:italic>Mtb<\/jats:italic>\n                  ) infection, CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells exhibit dysfunction with impaired cytotoxicity and limited localization to granuloma cores. Using knockout mice, adoptive-transfer models and validation in macaque and human datasets, we identified the nuclear receptor NR4A1 as a key restrainer of CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell immunity in tuberculosis (TB).\n                  <jats:italic>Mtb<\/jats:italic>\n                  -infected\n                  <jats:italic>Nr4a1<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  mice displayed reduced bacterial burden, attenuated pathology, higher lung CD8\n                  <jats:sup>+<\/jats:sup>\n                  \/CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cell ratios, and enhanced CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell effector functions. Bulk and single-cell RNA sequencing revealed suppression of gene expression program linked with exhaustion, and expansion of\n                  <jats:italic>Nkg7<\/jats:italic>\n                  <jats:sup>+<\/jats:sup>\n                  and\n                  <jats:italic>Granzyme<\/jats:italic>\n                  <jats:sup>+<\/jats:sup>\n                  cytotoxic CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell subsets in\n                  <jats:italic>Nr4a1<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  mice. Spatial analyses demonstrated increased infiltration of\n                  <jats:italic>Nkg7<\/jats:italic>\n                  <jats:sup>+<\/jats:sup>\n                  activated CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells in\n                  <jats:italic>Nr4a1<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  lesions. ChIP-qPCR showed NR4A1 binding to\n                  <jats:italic>Nkg7<\/jats:italic>\n                  promoter, and\n                  <jats:italic>Nkg7<\/jats:italic>\n                  knockdown abrogated the enhanced cytotoxicity of\n                  <jats:italic>Nr4a1<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells. Pharmacologic inhibition of NR4A1 reduced\n                  <jats:italic>Mtb<\/jats:italic>\n                  burden and pathology, and restored\n                  <jats:italic>Nkg7<\/jats:italic>\n                  expression and CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell infiltration in the lung. Together, these findings identify NR4A1 as a negative regulator of CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell\u2013mediated immunity in TB and suggest the NR4A1-NKG7 axis as a novel host-directed therapeutic target.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>A one-sentence summary of your paper<\/jats:title>\n                  <jats:p>\n                    NR4A1 suppresses CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell infiltration and cytotoxicity in TB lesions, and its inhibition enhances host resistance to\n                    <jats:italic>Mtb<\/jats:italic>\n                    infection.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.12.699051","type":"posted-content","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T18:35:19Z","timestamp":1768329319000},"source":"Crossref","is-referenced-by-count":2,"title":["NR4A1 limits CD8\n 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