Our laboratory is fascinated by the subset of T cells that naturally express 2 T cell receptors (TCRs). These dual receptor T cells were discovered in 1993, but presumed to be a relatively small proportion of T cells and have minimal effects on the development and reactivity of the T cell repertoire. However, work during my post-doctoral research identified dual TCR cells as having an unusual propensity to respond to allogeneic MHC ligands and subsequently being important contributors to in vitro and in vivo alloreactive responses in mice and human HSCT patients. Work from our laboratory has defined how dual TCR expression affects T cell development and homeostasis, as well as provided some clues to how these cells may utilize the second TCR in antigen recognition. Recent work has also defined the effects of dual TCR co-expression on thymocyte development and failure of central tolerance mechanisms to eliminate autoreactive TCR clonotypes from the repertoire. We are currently studying dual TCR cells to examine receptor signaling during development and activation and define TCR ligand biochemistry in these cells.
TCR recognition of peptide-MHC ligands, particularly examining peptide specificity and cross-reactivity in the context of alloreactivity, is of interest to our laboratory. The ability of the adaptive immune system to respond to antigens from pathogens, allogeneic tissues, or tumor cells while remaining tolerant to self-antigens is a long-standing interest. While TCR recognition of individual peptide-MHC complexes is highly specific, cross-reactivity and biochemical flexibility in ligand interaction are essential for T cell development and homeostasis. However, these properties also contain risk for heterologous immune responses that can result in pathology such as autoimmunity and alloreactivity. Notably, we have defined the role of specific recognition of endogenous peptide antigens in recognition of allogeneic MHC, reconciling long-stand paradoxical observations regarding the antigen-specific nature of T cell recognition, the fundamental concept of MHC restriction, and responses to allogeneic MHC. Current work is focused on examining TCRs that recognize individual ligands during immune responses in infection, transplantation, and anti-tumor responses and defining properties that differentiate successful from non-productive or pathogenic immune responses.