Studying alterations of T cell immune responses in the 17q12 deletion syndrome

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Project Summary/Abstract: The 17q12 deletion syndrome (17q12DS) is a chromosomal aberration with the deletion of a 1.4 megabases (Mb)‒spanning DNA sequence on the long arm of chromosome 17. Clinically, the 17q12DS is characterized by structural and/or functional abnormalities of the kidney, urinary and female genital tracts, maturity-onset diabetes of the young type 5 (MODY5), and neurodevelopmental disorders. Fifteen known genes are detected in the deleted 1.4 Mb of the 17q12DS; among these genes, the hepatocyte nuclear factor 1- beta (HNF1B) and LIM Homeobox 1 (LHX1) genes have been extensively characterized in relation to renal and urogenital malformations, MODY5, intellectual disability, and neuropsychiatric conditions in 17q12DS. However, there is a knowledge gap in our understanding of how other clinical features develop in relation to the deleted genes, especially those with less known functions, of 17q12DS. Of note, in our cohort of patients with 17q12DS, we have observed immune related disorders including severe atopic diseases like anaphylactic reactions to foods and infections requiring prolonged-course antibiotic therapy and/or hospitalizations, suggesting the possible immune dysregulation in 17q12DS, the point not addressed previously. Our preliminary data suggest that patients with 17q12DS have a substantially decreased frequency of CD4+ and CD8+ T cells producing the T helper (Th) 1 cytokine IFN-γ, the Th17 cytokine IL-17, and TNF-α compared to age-matched healthy controls (HCs) although both groups had similar frequencies of Th2 cytokine-producing T cells. These findings could account in part for our observations of severe infections in 17q12DS. The novel microRNA (miRNA) 2909, which is reported to regulate genes including IFNG, is encoded by the apoptosis-antagonizing transcription factor (AATF) gene that is deleted in 17q12DS. This raises the possible mechanistic implication of a heterozygous deletion of miR-2909 (hereafter miR-2909 deletion indicates this) in altering T cell immune responses in 17q12DS. The goal of our proposal is thus to test the overarching hypothesis that patients with 17q12DS have altered T cell immune responses driven in part by the deletion of miR-2909. Our study is the first one investigating the immune system in patients with 17q12DS who may have increased atopic diseases and infections. The goal of the proposal will be achieved with: Aim 1. Elucidate the characteristics of CD4+ and CD8+ T cells in patients with the 17q12 deletion syndrome using conventional and high-dimensional analyses. {As an exploratory approach, we will profile monocytes, natural killer (NK) cells, and B cell subsets to evaluate the possible global immune defect in 17q12DS. The relationship of these findings with clinical characteristics will be assessed.} Aim 2. Elucidate the role of miR-2909 in altering CD4+ and CD8+ T cell immune responses in the 17q12 deletion syndrome. The proposed study will advance our understanding on the immune system and its implication in developing clinical manifestations in patients with 17q12DS.