Genetically determined SKAP2 dosage controls T lymphocyte function

A locus linked to increased risk of Crohn’s disease (CD) contains 194 non-coding single-nucleotide polymorphisms in linkage disequilibrium, and a single gene encoding the SKAP2 adapter molecule, a known regulator of integrin activation in myeloid cells.

The minor allele, however, was specifically associated with increased SKAP2 expression in human T lymphocytes, possibly suggesting a previously unrecognized link between genetically determined SKAP2 dosage in T cells and CD pathogenesis. By analyzing T lymphocytes from homozygous donors for either the minor or major allelic variants, as well as primary T lymphocytes engineered to either lack SKAP2 expression or to express higher levels of endogenous SKAP2, we found that by controlling cell adhesion and migration, SKAP2 is a key modulator of T cell responses.