Decreased Th-1 CD4+ T cell function underlies recurrent respiratory infections in 17q12 deletion syndrome

The 17q12 deletion syndrome (17q12DS) is a chromosomal aberration with a heterozygous deletion of a 1.4 megabases (Mb)‒spanning DNA sequence on the long arm of chromosome 17. The well-known clinical characteristics of 17q12DS include abnormalities of the kidney and urinary tracts, as well as neurodevelopmental disorders. However, in our cohort of 37 subjects with 17q12DS, we observed increased atopic disorders and recurrent sinopulmonary infections requiring prolonged courses of antibiotic therapies and/ or hospitalizations, raising the possible immune dysregulation in 17q12DS, a point that has not been previously addressed. We thus tested the hypothesis that individuals with 17q12DS[KI1] have altered T-cell function, contributing to recurrent infections and[KI2] atopy. Here we found that individuals with 17q12DS had a substantially decreased frequency of CD4+ T cells producing the T helper (Th) 1 cytokine IFN[KI3]-g but not Th2 and Th17 cytokines compared to age-matched healthy controls (HCs). RNA seq analysis of CD4+ T cells revealed decreased levels of TBX21 encoding the Th1 transcription factor T-bet, IFNG, and other Th1 chemokine encoding genes in subjects with 17q12DS compared to HCs. These findings were validated at the protein level using flow cytometry and multiplex assay. Our study is the first to demonstrated immune alterations in 17q12DS characterized by decreased T-bet and its downstream molecules such as IFN-γ. These findings warrant further investigations into the underlying mechanisms, which would inform precision therapy for individuals with 17q12DS.