Decoding human T-cell allospecificity

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Summary CD8+ T cells are the main drivers of acute cellular rejection (ACR) of transplanted tissues. While T cells can recognize alloantigens directly (through direct responses to allo-HLA) as well as indirectly (through allopeptides bound to self-HLA), the major consensus is that direct recognition plays a major role in ACR. However, much is unknown about the biology of T cells responsible for direct ACR. For decades, alloreactive T cells have been viewed as either responding primarily to unique determinants on allo-HLA (HLA-centric responses), or to a plethora of non-self peptides presented by allo-HLA (peptide-centric). Recent data though has suggested that many alloreactive T cells are allospecific, responding to unique peptide/allo-MHC complexes present on the surface of allografts. Moreover, additional data suggests that alloreactive T cells may share reactivities with immunodominant viral epitopes and may in fact derive from pre-existing memory pools. While there is growing clarity around the structural features and immunological origins of alloreactive T cells, the lack of knowledge regarding the specificities of alloreactive T cells is a major reason for our limited biologic insight into T cell- mediated ACR. We are now poised to make a substantial breakthrough in this area and capitalize on it to better understand ACR and alloreactivity in general. In initial studies, using scRNA sequencing on biopsies and urine from several patients undergoing kidney transplant rejection, we found a remarkably and unexpectedly small number (~10-20/patient) of clonally expanded T cells with unique TCR CDR3 a/b sequences, and have confirmed their specificity towards the transplanted tissue. These expanded T cell clones persist for months in rejecting allografts, despite traditional anti-rejection therapy. The goal of this ambitious, high risk/high reward project is to identify the ligands recognized by alloreactive T cells within transplant biopsies, including both alloantigens and any cross-reactive viral epitopes and use this knowledge to begin decoding the immunobiology of ACR, identify possible therapeutic targets, and expand our understanding of the nature and origins of alloreactivity. Our specific hypotheses are that (i) the majority of clonally expanded allospecific TCRs recognize unique tissue restricted peptides presented by allo-HLA; (ii) many of these TCRs are also cross-reactive with viral epitopes presented by self-HLA; and (iii) identification of peptide targets will enable us to decode the transcriptomes of allospecific T cells in kidney allografts. Success in this multi-PI R21 proposal will pave the way for numerous, deeper, groundbreaking studies of alloreactivity, graft rejection, and novel therapeutic modulation of ACR.