UC San Diego

T cells that express 2 T cell receptors (TCRs), generated by productive rearrangement of both TCRα loci which pair with a single TCRβ, comprise ~10 percent of peripheral T cells in mice and humans. However, these dual receptor cells contribute 30-50% of the auto- and alloreactive T cell repertoires in naive mice and to acute graft versus host disease in patients post-transplant. The disproportionate contribution of dual TCR T cells to these processes suggests that they may contain a repertoire of TCRs with atypical reactivities. Our laboratory focuses on dual TCR T cells as a naturally-existing model to investigate thymic selection and T cell repertoire reactivity. In this work we investigate the highly alloreactive nature of dual TCR T cells by studying chronic graft versus host disease as a model linking thymic development to peripheral reactivity and disease pathology. We show that increased thymic production of dual TCR cells due to ineffective thymic selection results in an altered peripheral repertoire comprised of cells that are reactive to self. Patients with chronic graft versus host disease have a significantly increased and activated population of dual TCR cells that display a proinflammatory phenotype, as determined by targeted RNA sequencing. Using a mouse model of bone marrow transplant we were able to determine that defective negative selection due to thymic damage inflicted by pre-transplant conditioning was the cause of the increased dual TCR production. Lastly, we demonstrate a competitive advantage for dual TCR cells in lymphopenic conditions driven by their high affinity for self-peptide:MHC.