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Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency

Lookup NU author(s): Dr Venetia BigleyORCiD

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Abstract

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

Publication metadata

Author(s): Lévy R, Gothe F, Momenilandi M, et al

Publication type: Article

Publication status: Published

Journal: Journal of Experimental Medicine

Year: 2023

Volume: 220

Issue: 2

Print publication date: 06/02/2023

Online publication date: 14/12/2022

Acceptance date: 17/11/2022

Date deposited: 09/02/2023

ISSN (print): 0022-1007

ISSN (electronic): 1540-9538

Publisher: Rockefeller University Press

URL: https://doi.org/10.1084/jem.20220275

DOI: 10.1084/jem.20220275

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