Our research is focused on understanding the selection, activation and expansion of an autoreactive T cell repertoire in autoimmunity. We utilize tools such as HLA tetramers to predict and validate epitopes within candidate antigens and to directly identify and characterize antigen-specific CD4+ and CD8+ T cells. The lab’s studies currently focus on type 1 diabetes and rheumatoid arthritis. The overarching goal of our research is to develop an increasingly in depth knowledge of autoreactive T cell responses by examining the characteristics of epitope specific cells through robust multi-parameter assays and also at the single cell level. We seek to leverage that knowledge to develop clinically meaningful biomarkers and to reveal potential new avenues for therapy. Specific areas of research emphases include:
Epitope modification represents one important means through which the deletion of self-reactive T cells can be circumvented. Such modifications alter the primary sequence of self-peptides. This phenomenon serves to increase antigenic diversity and generates a special class of antigens that falls within ‘blind spots’ of central tolerance. More specifically post-translational modifications (PTMs) have the potential to increase the affinity of HLA/peptide interactions or HLA/peptide-TCR interactions depending on the positioning of the affected residue in relation to other HLA-anchoring residues along the peptide sequence. In particular, two modifications (citrullination and deamidation) have emerged that appear to have particular relevance in the etiology of autoimmunity. Our objective is to investigate the recognition of PTM epitopes as an important example of how the activation of self-reactive T cells contributes to the progression of autoimmune disease in human subjects. We seek to quantitate and phenotypically characterize T cells that recognize these disease relevant epitopes as a means of studying the natural history end etiology of autoimmune diseases.
Currently, the lab is implementing HLA tetramer assays to monitor changes in autoreactive T cell responses in the context of clinical trials and the natural history of autoimmune diseases. Recognizing that tetramer analysis is informative, but inherently limited by the volume of blood required we have developed a more robust multicolor tetramer assay to allow simultaneous analysis of multiple epitopes (or groups of epitopes) in a single staining tube. This approach can also be used to assess the level of cross reactivity between homologous epitopes. We have applied this multicolor approach characterize T cell responses in vaccines and subjects with autoimmune disease. Our ongoing work seeks to implement tetramer staining on highly multiplex platforms and to apply these methods to define immunological signatures that reflect disease states and to dissect these signatures to further our understanding of the underlying disease process.
Our group places a high value on collaboration, as manifested by our activity in groups such as the JDRF Biomarker Working Group, the Immunology of Diabetes Society T cell Workshop and nPOD and through formal and informal research collaborations with investigators across numerous areas of research. We are convinced that the future success of research will be crucially dependent on collaborative efforts that leverage the expertise of multiple researchers to address key questions through complementary techniques and approaches.