{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:41:27Z","timestamp":1789072887729,"version":"build-2803163510"},"reference-count":8,"publisher":"Rockefeller University Press","issue":"2","license":[{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005326","name":"Yale University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["227384\/Z\/23\/Z"],"award-info":[{"award-number":["227384\/Z\/23\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,3,2]]},"abstract":"<jats:p>Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a key immune checkpoint receptor that regulates T cell activation through ligand competition and transendocytosis. Heterozygous loss-of-function variants in CTLA4 result in CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI), characterized by immune dysregulation and autoimmunity. We report a multigenerational family carrying a novel heterozygous CTLA4 variant, c.654T&amp;gt;A (p.Tyr218*), which truncates the cytoplasmic tail. Affected individuals presented with recurrent infections and autoimmune manifestations. Patient T cells showed reduced CTLA-4 expression at baseline and after stimulation, suggesting impaired stability. Jurkat cells expressing CTLA-4 Y218* exhibited enhanced degradation, partially rescued by lysosomal inhibition, and reduced transendocytosis of CD80. Together, these findings suggest that the CTLA-4 p.Tyr218* variant compromises protein stability and ligand uptake, contributing to CTLA-4 haploinsufficiency and immune dysregulation. This work broadens the spectrum of CTLA4 variants and underscores the importance of the C-terminal cytoplasmic domain in CTLA-4 function and immune regulation.<\/jats:p>","DOI":"10.70962\/jhi.20250112","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T07:21:43Z","timestamp":1764660103000},"update-policy":"https:\/\/doi.org\/10.70962\/jhi.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Immune dysregulation from a novel CTLA-4 haploinsufficiency variant"],"prefix":"10.70962","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2472-7397","authenticated-orcid":true,"given":"Nina N.","family":"Brodsky","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03v76x132","id-type":"ROR","asserted-by":"publisher"}],"name":"Pediatric Genomics Discovery Program, Yale University School of Medicine 1 Department of Pediatrics, , New Haven, 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