{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:02:36Z","timestamp":1782280956570,"version":"3.54.5"},"posted":{"date-parts":[[2023,9,17]]},"group-title":"Immunology","reference-count":51,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,9,17]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  The increasing utilization of anti-PD-1 immune checkpoint blockade (ICB) has led to the emergence of immune-related adverse events (irAEs), including sicca syndrome. Interestingly, we found that the submandibular gland (SMG) of PD-1 deficient mice harbors a large population of CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells, reminiscing ICB induced sicca. This phenotype was also observed in the SMG of both NK cell-depleted C57BL\/6 animals and NK cell-deficient animals. Mechanistically, using mice conditionally deficient for PD-L1 in the NK cell lineage, we discovered that NK cells regulate CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell homeostasis via the PD-1\/PD-L1 axis in this organ. Importantly, single-cell RNA sequencing of PD-1 deficient SMG CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells reveals a unique transcriptional profile consistent with TCR activation. These cells have limited TCR diversity and phenotypically overlap with GzmK\n                  <jats:sup>+<\/jats:sup>\n                  CD8\n                  <jats:sup>+<\/jats:sup>\n                  T autoimmune cells identified in primary Sj\u00f6gren\u2019s syndrome patients. These insights into NK cell immunoregulation in the SMG, and the consequences of disrupted CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell homeostasis, provide opportunities for preventing the development of irAEs.\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>\n                        Elevated CD8\n                        <jats:sup>+<\/jats:sup>\n                        T cells in the submandibular gland (SMG) of PD-1 deficient mice parallel sicca-like irAEs seen in ICB patients.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        In addition to their previously described hyporesponsive phenotype, NK cells in the SMG regulate CD8\n                        <jats:sup>+<\/jats:sup>\n                        T cell homeostasis through the PD-L1\/PD-1 axis.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        PD-1 deficient SMG CD8\n                        <jats:sup>+<\/jats:sup>\n                        T cells display unique transcriptional profiles associated with proinflammatory functions, TCR activation, interferon stimulation, and exhaustion.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Oligoclonal expansion and similarities in TCR sequences indicate T cell activation and a preference for recognizing specific antigens.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2023.09.15.557930","type":"posted-content","created":{"date-parts":[[2023,9,17]],"date-time":"2023-09-17T17:35:12Z","timestamp":1694972112000},"source":"Crossref","is-referenced-by-count":3,"title":["PD-1 Mediated Regulation of Unique Activated CD8\n                  <sup>+<\/sup>\n                  T Cells by NK Cells in the Submandibular Gland"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4960-131X","authenticated-orcid":false,"given":"Samantha M.","family":"Borys","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9465-706X","authenticated-orcid":false,"given":"Shanelle P.","family":"Reilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Magill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0990-217X","authenticated-orcid":false,"given":"David","family":"Zemmour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7497-8488","authenticated-orcid":false,"given":"Laurent","family":"Brossay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023092106400652000_2023.09.15.557930v1.1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1303469"},{"key":"2023092106400652000_2023.09.15.557930v1.2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601099"},{"key":"2023092106400652000_2023.09.15.557930v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2015.11.007"},{"key":"2023092106400652000_2023.09.15.557930v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.03.007"},{"key":"2023092106400652000_2023.09.15.557930v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.09.082"},{"key":"2023092106400652000_2023.09.15.557930v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.09.076"},{"key":"2023092106400652000_2023.09.15.557930v1.7","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00256-06"},{"key":"2023092106400652000_2023.09.15.557930v1.8","doi-asserted-by":"publisher","DOI":"10.1007\/s00430-008-0077-2"},{"key":"2023092106400652000_2023.09.15.557930v1.9","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.3.1703-1717.2003"},{"key":"2023092106400652000_2023.09.15.557930v1.10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001254"},{"key":"2023092106400652000_2023.09.15.557930v1.11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.704862"},{"key":"2023092106400652000_2023.09.15.557930v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.108"},{"key":"2023092106400652000_2023.09.15.557930v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80089-8"},{"key":"2023092106400652000_2023.09.15.557930v1.14","doi-asserted-by":"publisher","DOI":"10.1177\/1758835920937612"},{"key":"2023092106400652000_2023.09.15.557930v1.15","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1703481"},{"key":"2023092106400652000_2023.09.15.557930v1.16","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2018-0823"},{"key":"2023092106400652000_2023.09.15.557930v1.17","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1412082"},{"key":"2023092106400652000_2023.09.15.557930v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2020.04.018"},{"key":"2023092106400652000_2023.09.15.557930v1.19","doi-asserted-by":"publisher","DOI":"10.1126\/science.291.5502.319"},{"key":"2023092106400652000_2023.09.15.557930v1.20","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20022125"},{"key":"2023092106400652000_2023.09.15.557930v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/srep39105"},{"key":"2023092106400652000_2023.09.15.557930v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cger.2016.08.007"},{"key":"2023092106400652000_2023.09.15.557930v1.23","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.7.4742"},{"key":"2023092106400652000_2023.09.15.557930v1.24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1112064108"},{"key":"2023092106400652000_2023.09.15.557930v1.25","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.7.1027"},{"key":"2023092106400652000_2023.09.15.557930v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/85330"},{"key":"2023092106400652000_2023.09.15.557930v1.27","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200324228"},{"key":"2023092106400652000_2023.09.15.557930v1.28","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.10.5538"},{"key":"2023092106400652000_2023.09.15.557930v1.29","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701231"},{"key":"2023092106400652000_2023.09.15.557930v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01197-z"},{"key":"2023092106400652000_2023.09.15.557930v1.31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.681941"},{"key":"2023092106400652000_2023.09.15.557930v1.32","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.167490"},{"key":"2023092106400652000_2023.09.15.557930v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/nature22383"},{"key":"2023092106400652000_2023.09.15.557930v1.34","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.68605"},{"key":"2023092106400652000_2023.09.15.557930v1.35","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15637"},{"key":"2023092106400652000_2023.09.15.557930v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.09.013"},{"key":"2023092106400652000_2023.09.15.557930v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.imm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