Rare dual TCR T cells contribute substantially to alloreactivity (141.2)

Abstract

Abstract T cell recognition of allogeneic MHC has long been recognized, though the nature of the alloreactive TCR repertoire is unknown. We hypothesize that the 1-3% of T cells expressing dual TCR due to incomplete allelic exclusion of TCRα are highly alloreactive due to non-thymically selected secondary TCR. Using the 4 available antibodies against TCRVα we observe an increased frequency of dual TCR T cells among alloreactive T cells in vitro. We quantitatively assessed the contribution of secondary TCR to the alloreactive repertoire by ELISPOT analysis; TCRA-C mice, incapable of expressing secondary TCRα, have a 50% decrease in alloreactive precursor frequency indicating secondary TCR contribute disproportionately to the alloreactive repertoire. We directly demonstrate expansion of the alloreactive repertoire by identification of a secondary non-thymically selected TCR with specific alloreactivity distinct from the primary TCR. The importance of dual TCR T cells is underscored by the dramatic increase of dual TCR among T cells mediating parent to irradiated F1 graft-vs.-host disease (GvHD); dual TCR comprised as much as 40% of peripheral T cells in mice with GvHD, compared to 3% observed in control mice. Together these studies convincingly demonstrate the importance of dual TCR T cells in alloreactivity. NIH AI061173 (PMA) and W.M. Keck Foundation Fellowship in Molecular Medicine (GPM).