Dissecting T Cell Developmental Defects in Down Syndrome

About This Grant

PROJECT SUMMARY / ABSTRACT This MPI R21 proposal directly addresses the objectives of the INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project, emphasizing the creation of innovative biological resources to advance Down syndrome (DS) research. DS is linked to widely dysregulated immune responses, including susceptibility to autoimmunity and infections, but most current research has focused on B cell hyperactivity and interferon-driven pathways, leaving the role of inadequate thymic selection—marked by reduced thymic output and premature thymic involution—largely uncharacterized. Our proposal posits that a fundamental gap in DS research is the absence of a comprehensive understanding of how these thymic defects drive peripheral immune dysfunction. To address this, we will build a well-annotated, deeply profiled biorepository of thymic samples from individuals with trisomy 21 and age-matched disomic controls, enabling a systematic examination of thymic education processes that may underlie the broader immunopathology seen in DS. Although murine models of DS have offered important insights into the genetics and pathology of trisomy 21, they are inherently limited by the fact that the extra copy of human chromosome 21 cannot be fully and precisely replicated in mice. Thymic development, in particular, depends heavily on self-antigens specific to each species, as immature thymocytes are “educated” through interactions with the host’s unique set of self-genes. By establishing a biorepository of human DS thymic tissue, we will circumvent these issues, enabling precise investigations into how an extra copy of chromosome 21 disrupts thymic selection and predisposes individuals with DS to immune dysfunction. To this end, we propose the following two goals. First, through a close collaboration with the Primary Children’s Hospital in Salt Lake City, we will create a comprehensive repository of thymic samples from infants with trisomy 21 and age-matched controls. All samples will undergo HLA genotyping, biological sex determination, and a thorough phenotypic analysis of both T-lineage and non–T- lineage cells, evaluating each thymocyte subset’s responsiveness to T cell receptor (TCR) stimuli at critical developmental checkpoints. Second, we will sequence the TCR repertoire at each developmental stage— evaluating both diversity and amino acid composition—and then compare these results with our existing in- house TCR datasets from individuals with autoimmune diseases and carriers of polymorphisms in genes critical for TCR repertoire formation. This approach will help us pinpoint meaningful similarities or differences among these groups. By filling critical knowledge gaps related to T-lineage ontogeny, our findings may reveal whether this underexplored aspect of thymic development in DS contributes to the documented immune dysfunction.