Analysis of Human Autoreactive T Cell Receptors in vivo

Contact PI: Ronald Gill, PhD, University of Colorado Denver (UC4 DK104223)

Maki Nakayama, MD, PhD, co-Investigator, University of Colorado Denver
Peter Gottlieb, MD, co-Investigator, University of Colorado Denver
Aaron Michels, MD, co-Investigator, University of Colorado Denver
John Kappler, PhD, co-Investigator, National Jewish Medical and Research Center

Start Date: September 30, 2014
End Date: June 30, 2019


Most evidence indicates that Type 1 Diabetes (T1D) results from T cell-dependent destruction of insulin producing beta cells within pancreatic islets. A major developmental focus of the Human Islet Research Network and Consortium on Modeling Autoimmune Interactions (HIRN-CMAI) is to generate ‘humanized’ mouse models suitable for studying human autoreactivity in vivo.  This is a challenging and ongoing goal of many research groups, including those at our own Center.  We perceive that one key current limitation of such animal models is the ambiguity in defining the specificity and function of defined human autoreactive T cell receptors (TCR). Over several years, a number of investigators have isolated a variety of candidate human autoreactive T cell lines and clones derived from T1D subjects.  However, the direct role of these differing self-antigen specific T cells in mediating islet beta cell injury remains poorly understood. Therefore, our group proposes to develop a comprehensive program to introduce a series of human autoreactive TCRs into suitable human HLA mouse models to interrogate autoreactivity in vivo.  To this end, we have developed collaborations from several investigators world wide to amass a number of islet-reactive T cells from which to harvest human autoreactive TCRs genetic sequences.  Our goal is to translate these candidate human TCRs into reproducible animal models by merging three major areas of expertise at our Institution:  1) Expertise in studying human autoreactivity in T1D, 2) Expertise in TCR structure and function and the introduction of TCR gene sequences into animals using ‘retrogenic’ technology, and 3) Extensive experience in small animal modeling to study T cell reactivity to both native and transplanted islets in vivo.




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