T cells respond to threats in an antigen-specific manner using somatically rearranged T cell receptors (TCRs) that recognize short peptide antigens (or targets) presented on major histocompatibility complex (MHC) proteins. A healthy human immune system is estimated to contain an enormous number (estimated to be 10⁶-10⁸) of unique T cells, each with a TCR that recognizes a unique antigenic target. The TCR-peptide-MHC interaction mediated between a T cell and its target cell dictates its function, and thereby influences its role in disease. The lack of approaches for antigen discovery has limited the fundamental understanding of the antigenic landscape the overall T cell response and thereby has impeded the development of targeted therapies. Our lab has recently made significant progress in the area of T cell antigen discovery. A novel high-throughput approach developed by us has demonstrated the ability to identify the target antigen of a given T cell. We propose to use this platform to address major questions in Immunology: What is the breadth of the T cell response in a given disease? How do the antigenic landscapes of T cell responses evolve over time? And What is the fundamental mechanistic basis of antigen recognition by TCRs?

Our studies will include characterizing the antigenic targets of CD8+ T cells and regulatory T cells in anti-tumor and autoimmune T cell responses and probing the mechanistic basis of cross-reactivity of T cells between self- and pathogen-derived targets. Building upon our previous work, we will also use engineered peptide-MHC receptors for modulating T cell responses in an antigen-specific manner. Furthermore, we will address one of the central challenges in immunology: Can we predict the antigenic target of a T cell based on the amino acid sequence of its TCR? We will develop experimental and computational approaches to decipher fundamental rules governing TCR-peptide-MHC interactions and develop a framework for predicting TCR ligands. Through these studies we aim to advance our fundamental understanding of the role of T cells in protective and pathogenic immunity and design novel strategies for immunotherapy. The benefit to public health includes development of targeted and thereby safer and more efficacious approaches to treat a wide range of afflictions including autoimmune disorders, infectious diseases, and cancers.

The main goals of the laboratory are:

1. Examine the shifting antigenic landscape of antitumor T cell responses by performing a systems-level analysis of the targets of T cell responses
2. Determine the fundamental rules of TCR-pMHC interactions and develop computational framework for predicting T Cell Receptor ligands
3. Investigate novel immunotherapies for autoimmune diseases by manipulating cell signaling pathways for desired therapeutic outcome