Variants in human CD48 lead to impaired T-cell immunity and increased inflammation

CD48 is a surface molecule with immunoregulatory functions. Following our initial report of a patient with a de novo heterozygous variant at amino acid S220 in the CD48 gene, we describe a second, unrelated patient with similar features of immune dysregulation and a missense change affecting the same residue. To further elucidate the specific pathogenic mechanisms of the identified variants, we reviewed patient records, analyzed patient-derived cells, and employed complementary in vitro and in vivo model systems, including transfected cell lines and CD48-deficient mice. We demonstrate that the variants are associated with altered distribution of CD48, characterized by diminished CD48 surface expression, intracellular retention, and activation of endoplasmic reticulum stress signaling. Patient T cells display increased susceptibility to apoptosis, reduced antiviral responses, and enhanced inflammation. Both patients exhibit T-cell lymphopenia, a restricted TCR repertoire diversity, and oligoclonal expansions consistent with antigen-driven selection. In parallel, virally-infected CD48-deficient mice recapitulate key aspects of the human phenotype, including delayed antiviral immune responses, impaired viral clearance and pronounced inflammation. We conclude that identified variants compromise CD48 cell-surface localization, impair T-cell survival and function, and predispose to inflammation, thereby highlighting the role of CD48 in immune regulation and the prevention of excessive inflammation.