{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:52:00Z","timestamp":1785433920013,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,28]]},"group-title":"Immunology","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH\/NIAID","award":["R21AI178184"],"award-info":[{"award-number":["R21AI178184"]}]},{"name":"NIH\/NIAID","award":["1R01AI183292-01"],"award-info":[{"award-number":["1R01AI183292-01"]}]},{"name":"NIH","award":["5F31CA294908-02"],"award-info":[{"award-number":["5F31CA294908-02"]}]},{"id":[{"id":"https:\/\/ror.org\/00k6e3143","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  CD8 T cells mediate protective immune responses. However, persisting antigens such as chronic viruses or tumors redirect CD8 T cell differentiation to a sub-optimal, epigenetically defined state called exhaustion. Exhausted T cells (T\n                  <jats:sub>EX<\/jats:sub>\n                  ) lose their ability to persist long-term and to initiate functional memory responses. Checkpoint inhibitor blockade temporarily restores effector functions, but immune reinvigoration is not long-lasting, due to the epigenetic stability of T\n                  <jats:sub>EX<\/jats:sub>\n                  . Therefore, epigenetic reprogramming of T\n                  <jats:sub>EX<\/jats:sub>\n                  leading to durable T cell responses is essential to improve disease control. Here, we demonstrate that a single microRNA (miR), miR-29a, epigenetically re-directs T\n                  <jats:sub>EX<\/jats:sub>\n                  differentiation and preserves T\n                  <jats:sub>EX<\/jats:sub>\n                  into a stem-like state, leading to long-term persisting progenitor T\n                  <jats:sub>EX<\/jats:sub>\n                  . MiR-29a rewires epigenetic maintenance programs, including downregulation of key exhaustion-associated regulators (Dnmt1, Dnmt3a, and Dnmt3b), alongside increased expression of progenitor- and stemness-associated genes such as Tcf7 and Il7r. These reprogrammed CD8 T cells are more sensitive to PD-L1 checkpoint blockade. Ectopic expression of miR-29a combined with aPD-L1 treatments enhances effector responses, while preserving T cell stemness. Together, our findings suggest that miR-29a can be leveraged to overcome current barriers to immune checkpoint blockade.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>MiR-29a rewires key exhaustion-associated epigenetic maintenance programs, while enhancing stemness-associated transcriptional circuits.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        MiR-29a drives extensive remodeling of accessible chromatin in T\n                        <jats:sub>EX<\/jats:sub>\n                        .\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        MiR-29a preserves newly generated progenitor T\n                        <jats:sub>EX<\/jats:sub>\n                        in a durable, epigenetically defined stem-like state with increased effector function.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        MiR-29a synergizes with aPD-L1; while miR-29a preserves progenitor T\n                        <jats:sub>EX<\/jats:sub>\n                        state, addition of aPD-L1 enhances the cytotoxic potential of these progenitor T\n                        <jats:sub>EX<\/jats:sub>\n                        cells.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.25.727439","type":"posted-content","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T06:40:16Z","timestamp":1780036816000},"source":"Crossref","is-referenced-by-count":0,"title":["MicroRNA-29a enhances and preserves stem-like CD8 T cell differentiation by regulating master epigenetic circuits of exhaustion"],"prefix":"10.64898","author":[{"given":"Xuebing","family":"Leng","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Miami, Miami, Florida"},{"name":"Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance A.","family":"Buchness","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Miami, Miami, Florida"},{"name":"Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine I.","family":"Rafie","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida"},{"name":"Cancer Biology Program, University of Miami, Miami, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis I.","family":"Vlantis","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida"},{"name":"Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana","family":"Ristin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Miami, Miami, Florida"},{"name":"Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel A.","family":"Gallardo","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Miami, Miami, Florida"},{"name":"Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supipi L.","family":"Auwardt","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Miami, Miami, Florida"},{"name":"Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha K.","family":"Khatwani","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida"},{"name":"Cancer Biology Program, University of Miami, Miami, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-De","family":"Tan","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuguang","family":"Ban","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, 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