My lab's research interests are focused on understanding the mechanisms of T cell activation in response to antigen. For our experiments, amino acid substitutions are introduced into the antigenic peptide and the effects of these altered peptides on the immune response are assessed. It is apparent that the T cell receptor can interact with a spectrum of variant peptide ligands, which is then translated into distinct T cell signals and responses. Every facet of T cell biology and its relationship to disease are impacted by this observation. Currently, we are studying how alterations in the stability of antigenic peptide interaction with MHC molecules affect the level of the T cell response. These less stable variant peptides are found in viral escape mutants, tumor associated antigens, and autoimmune antigens. For viral escape mutants and tumor antigens the goal is to improve the peptide antigens immunogenicity to optimize the T cell response. In contrast, the autoimmune antigens are being weakened in terms of their ability to bind MHC and tested in an animal model of multiple sclerosis called EAE in order to lessen the severity of autoimmune disease. For these experiments, we are also interested in characterizing the activity level of negative signaling molecules such as the SHP-1 tyrosine phosphatase to delineate the mechanism(s) at work during the T cell response against weak antigens. Thus, understanding the interaction between peptide ligand and the T cell receptor is significant for all areas of T cell biology.
My lab’s research interests are focused on understanding the mechanisms of T cell activation in response to peptide:MHC antigens with focus on models of autoimmune disease and viral infection. Overall, our work seeks a better understanding of how T cells respond to antigen with a goal that one can intervene to prevent autoimmune disease or improve anti-viral immune responses. We currently are assessing T cell antigen recognition in several systems including animal models of autoimmune disease for multiple sclerosis (EAE), type 1 diabetes, and viral infection. In addition, we have studies analyzing T cell affinity in T cells from MS patients. To understand TCR recognition of antigens and variant antigens, we have been collaborating for >10 years on defining the two dimensional (2D) binding kinetics of TCR for peptide:MHC with Dr. Cheng Zhu at Georgia Tech. This collaboration has resulted in a series of studies defining the 2D binding kinetics for the CD8+ and CD4+ T cell responses. This 2D technology allowed us to demonstrate a correlation between 2D binding kinetics and the potency of response to a panel of variant peptides. Importantly, this data greatly alters our understanding of antigen recognition revealing a TCR with fast on rates, high affinity, and rapid off rates, which seems especially well suited for its purpose of scanning pMHCs for antigen (Nature 2010). In the case of polyclonal responses, the 2D technology revealed a greater diversity of affinities at the peak of the immune response and a greater frequency of lower affinity tetramer negative TCRs than one might predict (JEM 2011). Thus, understanding the interaction between antigen and the T cell receptor is significant for understanding all areas of T cell biology including the immune responses during autoimmune disease and viral infection.