To elucidate the mechanisms by which type 1 diabetes-associated genes; IFIH1, TYK2, IKZF4, as well as total genetic risk, impart functional immunoregulatory abnormalities that result in expansion of self-reactive adaptive immune cells, defective regulatory/effector mechanisms in T cells, inflammatory antigen presenting cells, and abnormal immune function in T cells and B cells.

Newly proposed studies will identify the inflammatory cues that draw immune cells into islets for disease initiation (Project 1); probe the motility of immune cells through inflamed vasculature to the target organ and antigen priming sites within secondary lymphatics (Project 2); and characterize the T1D-associated adaptive immune signatures in blood and immune tissues (Project 3).

The overall hypothesis of the renewed P01 states: 1) the impact of T1D-risk variants will vary by tissue, cell subset, and activation state, and 2) risk variants, cellular stress, and defects in immunologic pathways are key to engender the autoimmune destruction of pancreatic B-cells that results in T1D.

Inclusion Criteria: able to have blood drawn -

Exclusion Criteria: none

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Individuals age 0 to 100 with or without a diagnosis of type 1 diabetes and able/willing to have a blood draw

the data generated from the proposed studies will be presented at national or international conferences and published in a timely fashion. Investigators associated with this P01 have a record of publishing in pre-print servers and favoring open-access journals, when appropriate. The investigator will implement field standard, open-source tools including those developed by investigators on this proposal for data processing. Importantly, raw data, processed data, and metadata will be stored locally as well as deposited on public databases as detailed further below. All final peer-reviewed manuscripts that arise from this proposal will be submitted to the digital archive PubMed Central. Evidence of this is provided in the attached biosketches.