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We describe a cohort of six individuals who have function-disrupting variants in\n                  <jats:italic>GPR174<\/jats:italic>\n                  and a clinical phenotype of lymphadenopathy and autoimmunity. Histological analysis of two patient lymph nodes revealed necrotizing lymphadenitis and lymphoproliferation resembling Kikuchi-Fujimoto disease. In-depth analysis of three patients and related carriers revealed overaccumulation of CD8 terminally differentiated effector memory cells re-expressing CD45RA (T\n                  <jats:sub>EMRA<\/jats:sub>\n                  ). Patient cells and GPR174- deficient CD8 T cells generated from controls showed less repression of proliferation by the GPR174 ligand lysophosphatidylserine (lysoPS) and an effector-biased gene expression program. GPR174-deficient CD4 T cells were resistant to lysoPS-mediated suppression of IL2 production. In mice, chronic viral infection led to over-accumulation of GPR174-deficient effector CD8 T cells. We describe an inborn error of immunity associated with dysregulated lymphocyte responses that we propose predisposes to exaggerated lymphoproliferation and autoimmunity following viral infection.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>Six individuals with function-disrupting variants in the G-protein coupled receptor GPR174 provide insight into its immunoregulatory role. GPR174 loss emerges as a potential genetic risk factor for histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease) and autoimmunity via defects in T cell regulation.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.14.26357774","type":"posted-content","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T18:00:13Z","timestamp":1784311213000},"source":"Crossref","is-referenced-by-count":0,"title":["Human GPR174 deficiency drives polyclonal lymphoproliferative disease via defects in T cell function"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3431-2163","authenticated-orcid":false,"given":"Yun-Han","family":"Huang","sequence":"first","affiliation":[{"name":"Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA"},{"name":"Division of Rheumatology, Department of Medicine, University of California, San Francisco, CA 94143, 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