Understanding the T Cell Repertoire in Autoimmune Diseases Using High-dimensional Single-cell Analysis of Antigen-specific CD4+ and CD8+ T cells

Despite approvals of new medicines to treat patients with autoimmune diseases, the development of durable new disease modifying therapies that address the underlying causes of disease remain elusive.

To advance the development of new diagnosis and treatment strategies for antigen-specific T cell-driven autoimmune diseases, new insights into disease-associated T cell specificities will be required.  We have developed the three integrated technologies of our DECODE^TM platform to discover disease-associated TCR-pMHC specificities and further elaborate the functionality of associated T cell clonotypes.

Using DECODE Antigen, we experimentally determine peptides that are well-presented by class II MHC.  DECODE Synapse profiles the reactivities and phenotypes of primary T cells using hundreds of DNA barcoded multimers.  With DECODE TCR, we de-orphan or assess the cross-reactivity of high-value TCRs isolated from disease tissue using thousands to millions of genetically encoded epitopes.

To develop our Autoimmune Synapse Maps, we apply the DECODE platform to analyze T cells derived from the peripheral blood, spleen, lymph nodes, and disease-associated tissue of carefully selected cohorts of patients and healthy donors. 

Our synapse map of HLA-A*02:01 in Type 1 Diabetes includes dozens of novel epitopes enriched in T1D patients.  Multiple clonotypes activated by these shared epitopes are TNF / IFN producing, effector memory cells. We have also begun to develop synapse maps on multiple class I and class II alleles in T1D, Multiple Sclerosis, and vitiligo.  Our discovery platform has the potential to provide an approach to identify the antigens that matter for antigen-specific tolerizing therapies.