{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T17:23:46Z","timestamp":1772040226782,"version":"3.50.1"},"posted":{"date-parts":[[2025,7,14]]},"group-title":"Immunology","reference-count":29,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T00:00:00Z","timestamp":1752451200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["1R15AI169400-01A1"],"award-info":[{"award-number":["1R15AI169400-01A1"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100018510","name":"Texas Woman's University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100018510","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100018510","name":"Texas Woman's University","doi-asserted-by":"crossref","award":["Center for Student Research Grants and Experiential Student Scholar Grant"],"award-info":[{"award-number":["Center for Student Research Grants and Experiential Student Scholar Grant"]}],"id":[{"id":"10.13039\/100018510","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Aberrant CD8 T-cell differentiation contributes to the pathogenesis of autoimmune diseases, and immune-mediated tissue damage. However, the molecular mechanisms that prevent premature effector T cell programming in humans remain incompletely defined. Signal regulatory protein gamma (SIRP\u03b3) is selectively expressed on T-cells in the human immune system. Notably, genetic variants associated with reduced SIRP\u03b3 expression have been linked to increased risk of immune-mediated diseases, including type 1 diabetes and multiple sclerosis, but the contribution of SIRP\u03b3 to CD8 T-cell dysregulation in these contexts remains unclear.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To determine how inter-individual variation in SIRP\u03b3 expression influences immune homeostasis and CD8 T-cell effector programming.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Peripheral blood CD8 T-cells from healthy donors were analyzed for SIRP\u03b3 expression and associated differentiation phenotypes. Na\u00efve CD8 T-cells were purified and subjected to siRNA-mediated knockdown of\n                    <jats:italic>SIRPG<\/jats:italic>\n                    , followed by suboptimal TCR stimulation. Differentiation status, transcription factor expression, and effector cytokine production were measured using flow cytometry. CD47 blockade was used to assess ligand dependency.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Low SIRP\u03b3 expression on CD8 T-cells was associated with increased frequencies of CD27\u207bCD45RO\u207a effector-like and CD27\u207bCD45RO\u207b terminally differentiated CD8 T-cells. SIRPG knockdown induced effector-like differentiation, with increased CD45RO and T-bet expression and elevated TNF-\u03b1, IFN-\u03b3, and Granzyme B production. This effect was not recapitulated by CD47 blockade, suggesting a CD47-independent regulatory mechanism.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>SIRP\u03b3 serves as a negative regulator of CD8 T-cell effector differentiation under suboptimal stimulation. Inter-individual variation in its expression may influence susceptibility to immune dysregulation, positioning it as a potential biomarker and therapeutic target.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.09.663913","type":"posted-content","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T21:40:38Z","timestamp":1752529238000},"source":"Crossref","is-referenced-by-count":1,"title":["SIRP\u03b3 modulates effector differentiation of human CD8 T Cells under suboptimal TCR stimulation: implications for immune homeostasis and autoimmunity"],"prefix":"10.64898","author":[{"given":"Megan","family":"Morse","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xanthie","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika","family":"DeLaRosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sierra","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juma","family":"Shanil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sushmita","family":"Sinha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025071713004504000_2025.07.09.663913v1.1","doi-asserted-by":"crossref","unstructured":"Casadevall A , Pirofski LA . 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