Deleterious germline CARD11 gain-of-function variants alter human B-cell and CD4⁺ T-cell differentiation and function

CARD11 is a scaffold protein expressed primarily in hematopoietic tissues, shaping key processes in B and T cells via regulation of Ag-linked signaling pathways, including NF-κB, mTOR, JNK, and AKT. 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’ 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 naïve 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.