PROJECT SUMMARY/ABSTRACT This is a request for an Administrative Supplement for the INCLUDE Project for R01 AI166835 “Mechanistic and functional dissection of inflammaging in Down syndrome” in accordance with NOT-OD-22-137. The overarching goal of the parent grant is to advance our understanding of immune aging and immune response in DS. The proposed studies for the Administrative Supplement are within the scope of the active parent grant, focused on Down syndrome (DS) and address INCLUDE Project priorities Component 1 (Targeted high risk – high reward basic science studies highly relevant to DS) and Component 2 (Assembly of a large cohort of individuals with DS across the lifespan to perform deep phenotyping and study co-existing conditions). Our central hypothesis is that the immune features linked to impaired function in people with DS represent a subset of globally dysregulated features and are driven by cell-intrinsic and/or cell-extrinsic mechanisms. This hypothesis is based on the following: 1) Studies in vaccine response and in autoimmunity showing that the phenotype of antigen-specific cells is a subset of memory cell phenotypes, and 2) our data showing that immune features dysregulated in people with DS can be dysregulated by either cell-intrinsic mechanisms (e.g. DYRK1A) or cell-extrinsic mechanisms (e.g. IL-6). We expect our proposed studies in people with DS to better define vaccine-specific cells and the mechanisms underlying their dysregulation, thus providing key scientific foundation to improve vaccine response and, more broadly, immune function in this group. Our objectives for the Administrative Supplement are: 1) Enhance our existing DS biorepository by improving phenotypic data collection and curation and including more individuals with mosaic DS (Component 2), 2) Use phenomics to broadly identify CD4 T cell features dysregulated by cell-intrinsic vs cell-extrinsic mechanisms in people with DS (Component 1), and 3) Define dysregulation of vaccine-specific B cells in people with DS (Component 1). The proposed work leverages our group's published success in developing a cohort of individuals with DS and in building new tools to interrogate immune landscape and antigen-specific cell phenotype. It leverages many resources from the parent grant including cohorts (Aim 1a and 3), samples (Aim 3), postdoc effort (Aim 2 & 3), and computational analysis effort (Aim 2 and 3A). The proposed studies take advantage of interim experimental advances we have made to synergistically extend parent grant studies, thus promising synergistic return on investment (Aims 2 and 3). This is particularly important considering the limited nature of participants and samples. Importantly, we have built in plans to share tools and information from the proposed studies via the INCLUDE Data Hub. Thus, all the proposed studies are directly responsive to the RFA and are likely to significantly advance our understanding of immune dysregulation in people with DS ...