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We report that SIRP\u03b3 expression varies substantially across individuals and stratifies CD8 T cell differentiation states. Individuals with low SIRP\u03b3 expression exhibit an increased frequency of CD27\u2212CD45RO+ effector-like and CD27\u2212CD45RO\u2212 terminally differentiated CD8 T cells, while high expressors retain a predominance of na\u00efve and central memory cells. To investigate the functional role of SIRP\u03b3, we performed small interfering RNA\u2013mediated knockdown in na\u00efve human CD8 T cells. Under suboptimal TCR stimulation, SIRPG knockdown drove robust effector-like differentiation marked by increased CD45RO expression, T-bet upregulation, and enhanced production of TNF-\u03b1, IFN-\u03b3, and granzyme B. This phenotype was not recapitulated by CD47 blockade, indicating that SIRP\u03b3 modulates differentiation through a CD47-independent mechanism. These findings identify SIRP\u03b3 as a negative regulator of CD8 T cell effector programming under limiting stimulatory conditions. Interindividual variability in SIRP\u03b3 expression may influence immune homeostasis and susceptibility to immunopathology, highlighting SIRP\u03b3 as a potential therapeutic target in settings of dysregulated T cell responses.<\/jats:p>","DOI":"10.1093\/immhor\/vlag027","type":"journal-article","created":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T17:33:44Z","timestamp":1782063224000},"source":"Crossref","is-referenced-by-count":1,"title":["SIRP\u03b3 limits effector differentiation of human CD8 T cells in response to subthreshold TCR-signaling"],"prefix":"10.1093","volume":"10","author":[{"given":"Megan","family":"Morse","sequence":"first","affiliation":[{"name":"Department of Biology, Texas Woman\u2019s University , Denton, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xanthie","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Biology, Texas Woman\u2019s University , Denton, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Delarosa","sequence":"additional","affiliation":[{"name":"Department of Biology, Texas Woman\u2019s University , Denton, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sierra","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Biology, Texas Woman\u2019s University , Denton, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juma","family":"Shanil","sequence":"additional","affiliation":[{"name":"Department of Nutrition Sciences, Texas Woman\u2019s University , Denton, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9342-7424","authenticated-orcid":false,"given":"Sushmita","family":"Sinha","sequence":"additional","affiliation":[{"name":"Department of Biology, Texas Woman\u2019s University , Denton, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,21]]},"reference":[{"key":"2026110312321955800_vlag027-B1","doi-asserted-by":"publisher","first-page":"e00636","DOI":"10.1128\/IAI.00636-17","article-title":"What is a host? 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