Research

TCR Alloreactivity

The “identity” and functionality of T cells is primarily determined by the antigenic specificity of the T cell receptor (TCR). The TCR is a heterodimeric protein that enables highly sensitive and specific recognition of peptide antigens by T cells, underpinning adaptive cellular immune function. Our laboratory is particularly interested in examining peptide specificity and cross-reactivity driving recognition of non-self tissues (alloreactivity). While TCR recognition of individual pMHC 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. Current work is focused on examining the specific recognition of pMHC ligands driving pathologic T cell alloreactivity in transplantation and developing approaches to leverage this information for precision medicine approaches to reduce transplant rejection and graft versus host disease.

Dual TCR T Cells

Our laboratory studies the subset of T cells that naturally co-express 2 T cell receptor (TCR) clonotypes. By developing novel models and tools, we have demonstrated that these dual TCR cells are a significant portion (~16%) of the T cell repertoire in mice and humans. Importantly, we have demonstrated that dual TCR cell expression drives distinct biology, including promoting T cell alloreactivity (including pathologic graft versus host disease in human patients), promoting thymopoiesis and T cell development, and enhancing recognition of tumor NeoAntigens. Current work focuses on dissecting the biochemistry of pMHC ligand recognition and the induction of proximal TCR signaling by dual TCR cells.

Transplant Immunogenetics and Histocompatibility

T cell responses to allogeneic (non-self) tissues are approximately 100-1000-fold more robust than responses against pathogens. This is driven by the fact that human populations have astounding variation (>30,000 characterized protein-coding variants) in the genes encoding the classical Major Histocompatibility Complex (MHC) molecules (human ortholog HLA), which are responsible for presenting peptide antigens to T cells to initiate immune responses. The majority of known genetic variation in HLA is focused in the regions encoding the peptide-binding domains, which determines differential capability to bind and present peptide antigens. Our laboratory works to understand how to characterize this genomic variation and test the potential impacts on T cell responses in transplantation and cancer immunotherapy.