{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T14:46:06Z","timestamp":1784126766066,"version":"3.55.0"},"posted":{"date-parts":[[2023,12,23]]},"group-title":"Immunology","reference-count":64,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,12,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Unlike in infection and cancer, T cell exhaustion in autoimmune disease has not been clearly defined. Here we set out to understand inhibitory protein (PD-1, Tim3, CTLA4, Lag3) expression in CXCR5- and CXCR5+ CD8 and CD4 T cells in systemic lupus erythematosus. CXCR5+ CD8 and CD4 T cells express PD-1 and engage B cells in germinal center reactions, leading to autoantibody formation in autoimmunity. We hypothesized that CXCR5+ CD8 T cells develop an exhausted phenotype as SLE autoimmunity expands from initial to chronic, self-perpetuating disease due to chronic self-antigen exposure. Our results indicate that there is no exhaustion frequency differences between sexes, although disease kinetics vary by sex. CXCR5+ CD8 T cells express primarily IFN\u03b3, known to promote autoimmune disease development, whereas CXCR5-CD8 T cells express TNF\u03b1 and IFN\u03b3 as disease progresses from 2-6 months. Tim3 is the highest expressed inhibitory marker for all CD4 and CD8 T cell populations demonstrating potential for terminally exhausted populations. CTLA4 expression on CD4 T cells suggests potential tolerance induction in these cells. We identified exhaustion phenotypes within autoimmune disease that progress with increasing lupus erythematosus severity and possibly provide a feedback mechanism for immunological tolerance.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"order\">\n                    <jats:list-item>\n                      <jats:p>CXCR5- and CXCR5+ CD8 T cells expand with rate of disease in SLE mouse model.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>CXCR5+ CD8 T cells are low contributors to TNF\u03b1 disease progression unlike CXCR5-CD8 T cells but may increase disease mechanisms through high IFN\u03b3 production.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Inhibitory markers upregulate in frequency with the highest amounts seen in Tim3+ populations. Tim3+Lag3+ expression may be an indicator of terminal differentiation for all populations.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Inhibitory marker expression frequency was unrelated to sex.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2023.12.23.573167","type":"posted-content","created":{"date-parts":[[2023,12,23]],"date-time":"2023-12-23T19:20:11Z","timestamp":1703359211000},"source":"Crossref","is-referenced-by-count":3,"title":["T cell exhaustion dynamics in systemic autoimmune disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2314-6689","authenticated-orcid":false,"given":"Christi N.","family":"Turner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6879-4439","authenticated-orcid":false,"given":"Juan","family":"Camilo Sanchez Arcila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah","family":"Huerta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avi Rae","family":"Quiguoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0707-964X","authenticated-orcid":false,"given":"Kirk D.C.","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5443-0733","authenticated-orcid":false,"given":"Katrina K.","family":"Hoyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023122723001135000_2023.12.23.573167v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27500"},{"key":"2023122723001135000_2023.12.23.573167v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01210-5"},{"key":"2023122723001135000_2023.12.23.573167v1.3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.955038"},{"key":"2023122723001135000_2023.12.23.573167v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.11.028"},{"key":"2023122723001135000_2023.12.23.573167v1.5","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.156341"},{"key":"2023122723001135000_2023.12.23.573167v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111606"},{"key":"2023122723001135000_2023.12.23.573167v1.7","doi-asserted-by":"publisher","DOI":"10.1172\/jci120859"},{"key":"2023122723001135000_2023.12.23.573167v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0221-9"},{"key":"2023122723001135000_2023.12.23.573167v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/nri3862"},{"key":"2023122723001135000_2023.12.23.573167v1.10","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-016-0160-z"},{"key":"2023122723001135000_2023.12.23.573167v1.11","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21197357"},{"key":"2023122723001135000_2023.12.23.573167v1.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1712107115"},{"key":"2023122723001135000_2023.12.23.573167v1.13","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/8.5.765"},{"key":"2023122723001135000_2023.12.23.573167v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.103020"},{"key":"2023122723001135000_2023.12.23.573167v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2021.102690"},{"key":"2023122723001135000_2023.12.23.573167v1.16","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701079"},{"key":"2023122723001135000_2023.12.23.573167v1.17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00858"},{"key":"2023122723001135000_2023.12.23.573167v1.18","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401161"},{"key":"2023122723001135000_2023.12.23.573167v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/nature19330"},{"key":"2023122723001135000_2023.12.23.573167v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/nature19317"},{"key":"2023122723001135000_2023.12.23.573167v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.09.031"},{"key":"2023122723001135000_2023.12.23.573167v1.22","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02121-20"},{"key":"2023122723001135000_2023.12.23.573167v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.11.002"},{"key":"2023122723001135000_2023.12.23.573167v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23356-w"},{"key":"2023122723001135000_2023.12.23.573167v1.25","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1981.tb00343.x"},{"key":"2023122723001135000_2023.12.23.573167v1.26","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.5.2844"},{"key":"2023122723001135000_2023.12.23.573167v1.27","unstructured":"Kassambara A. 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