Heterogeneity and Plasticity of Alloreactive T Cells in Human Intestinal Allografts: New Insights into Tissue Residency and Immune Tolerance after Transplantation

We carried out single cell analysis of recipient T cells in the intestinal graft mucosa late post-Tx (626-1764 days after intestinal transplantation) in the presence and absence of rejection (persistent acute rejection or chronic rejection) by integrating pre- and post-Tx mixed lymphocyte reaction (MLR)-defined alloreactivity with T cell clonotype and RNA profiling. Our data reveal heterogeneity within the allograft of pre-existing HvG-reactive T cells that can have the resident memory T cell (TRM), cytotoxic TRM/effector T (Teff), nonTRM, follicular helper T cell (Tfh), and regulatory T cell (Treg) phenotypes. We further demonstrated distinct contributions of pre-existing host-versus-graft (HvG)-reactive T cells that potentially became tolerant in allografts and were dominated by TRM transcriptional profiles in quiescent but not rejecting grafts. Moreover, we identified de novo HvG-reactive T cells in post-Tx ileal grafts with a transcriptional profile that was highly skewed to activated cytotoxic effectors in rejecting, but not quiescent, grafts. Taken together, our study provides novel insights to the tissue residency and immune tolerance of alloreactive T cells in the graft after human SOT and a deeper understanding of TRM biology in humans.