Project Summary/Abstract The immune system becomes functionally impaired with aging (inflammaging), impacting risk and outcome of infection, vaccination, cancer, cardiovascular disease and autoimmunity. Individuals with Down syndrome (DS) exhibit clinical, cellular and biochemical features of inflammaging, including increased autoimmunity, decreased naïve T cells and increased pro-inflammatory cytokines. We developed a novel unbiased approach to analyze immune architecture in people with DS and quantitatively showed that people with DS exhibit advanced immune aging beginning in childhood driven in part by dysregulation of naïve CD4+ T cells. This approach showed shared features of advanced immune aging in DS and other autoimmune disease, suggesting functional relevance and overlap. Therefore, understanding (i) how advanced immune aging explains impaired functional immune responses in DS, and (ii) how dysregulation of naïve CD4+ T cells contributes to advanced immune aging, will help us develop novel therapeutic strategies to address immune defects in DS. Moreover, this understanding will help us identify subsets of the general population who may benefit from similar therapeutic strategies. This also establishes a basis to understand which genes on chromosome 21 drive advanced immune aging, with attendant mechanistic and translational implications. We hypothesize that advanced immune aging impairs immune responses by dysregulating naïve CD4+ T cells via cell-intrinsic and cell-extrinsic pathways. We propose key experiments here to advance our understanding of immune aging and immune response in DS. Our specific aims are: 1: Dissecting mechanistic features of naïve CD4+ T cell dysregulation in DS-inflammaging. We will leverage a novel DS biorepository that I helped establish at BRI to examine how DS impacts CD4+ T cell biology in the absence of confounding immune disorders. We will use in vitro assays coupled with RNAseq to identify and test candidate mechanisms. We will study individuals with mosaic DS to provide unique insight to dissect the cell-intrinsic roles of trisomy 21 in CD4+ T cell dysregulation in vivo. 2: Interrogate phenotypic and functional features of DS-inflammaging in vivo. We will use our immune cellular clock to quantitatively understand how inflammaging impacts vaccine response in people with DS and controls. We will also examine robustness of our DS-inflammaging findings in an independent cohort and follow our original cohort longitudinally to evaluate temporal progression of DS-inflammaging.

Project Narrative The proposed research is relevant to public health because it interrogates how immune aging impairs functional response to vaccination and how dysregulation of CD4+ T cells drives advanced immune aging, leveraging Down syndrome as a genetic model. This knowledge would establish the foundation to identify the patients, both with and without Down syndrome, who would benefit from altered vaccination strategies, and novel therapeutics to attenuate advanced immune aging, with likely utility across a broad spectrum of immune- related conditions. Thus, the proposed research is relevant to the part of NIH’s mission pertaining to reducing illness and disability.