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Heterozygous, gain-of-function (GOF) variants in its encoding gene, CARD11, are implicated in a human disorder characterized by frequent upper respiratory infections, poor responses to polysaccharide vaccines, vulnerability to certain opportunistic viruses, and polyclonal B-cell expansion, likely predisposing these patients to lymphoma. Over the past decade, several studies have elucidated some of the B-cell functional defects that likely underlie the patients\u2019 infectious phenotype. However, the potential contributions of CARD11 GOF variants to subpopulations of T cells have not been explored in detail. Therefore, our study sought to investigate the effect of increased CARD11 activity on the development, maturation, activation, differentiation, and effector function of adaptive lymphocytes from a cohort of five individuals harboring monoallelic CARD11 GOF variants through detailed ex vivo immunophenotyping and in vitro analyses. Our findings revealed intrinsic requirements for CARD11 in activation, differentiation, and effector function of human na\u00efve B cells. Contrary to previous reports, intact CARD11 activity is also required for multiple aspects of CD4+ T-cell homeostasis alongside its notable role in the humoral immune response. Overall, these results shed light on mechanisms underlying disease pathogenesis due to not only CARD11 GOF variants but also LOF variants and reveal opportunities to consider targeted therapies in CARD11 GOF patients.<\/jats:p>","DOI":"10.1093\/cei\/uxag034","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T11:52:16Z","timestamp":1781178736000},"source":"Crossref","is-referenced-by-count":0,"title":["Deleterious germline\n                    <i>CARD11<\/i>\n                    gain-of-function variants alter human B-cell and CD4+ T-cell differentiation and function"],"prefix":"10.1093","volume":"220","author":[{"given":"Tina","family":"Nguyen","sequence":"first","affiliation":[{"name":"Garvan Institute of Medical Research , Darlinghurst, NSW ,","place":["Australia"]},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney , Kensington, NSW ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa A","family":"Kallarakal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences , Bethesda, MD ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackie L","family":"Ludgate","sequence":"additional","affiliation":[{"name":"Department of Haematology, Dunedin School of Medicine, University of Otago , Dunedin ,","place":["New Zealand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian M","family":"Morison","sequence":"additional","affiliation":[{"name":"Department of Haematology, Dunedin School of Medicine, University of Otago , Dunedin ,","place":["New Zealand"]},{"name":"Awanui Labs , Dunedin ,","place":["New Zealand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen C","family":"Su","sequence":"additional","affiliation":[{"name":"Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, Intramural Research Program, NIAID, NIH , Bethesda, MD ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swadinhya","family":"Arjunaraja","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences , Bethesda, MD ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8728-6691","authenticated-orcid":false,"given":"Andrew L","family":"Snow","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences , Bethesda, MD ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy S","family":"Ma","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research , Darlinghurst, NSW ,","place":["Australia"]},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney , Kensington, NSW ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5360-5180","authenticated-orcid":false,"given":"Stuart G","family":"Tangye","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research , Darlinghurst, NSW ,","place":["Australia"]},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney , Kensington, NSW 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