Trogocytosis-derived regulatory cluster of differentiation 8−positive T cells facilitate induction of immune tolerance after lung transplantation

<h2>Abstract</h2><h3>Objective</h3> Donor-specific regulatory T cells are crucial for establishing immune tolerance in lung transplantation. We sought to elucidate the specific mechanisms by which major histocompatibility complex class II (MHC-II⁺) trogocytosis Tregs induce transient immune tolerance in lung transplantation. <h3>Methods</h3> A rat lung transplantation model with spontaneous tolerance was established. CD8⁺CD45RCl^ow Tregs and plasmacytoid dendritic cells (pDCs) were isolated by magnetic separation and characterized by flow cytometry, cytokine profiling, and confocal microscopy. Mixed lymphocyte reactions and targeted interventions were used to dissect the mechanisms governing MHC-II acquisition and the involvement of the interferon-gamma (IFN-γ)/indoleamine 2,3-dioxygenase (IDO) signaling axis. Adoptive transfer experiments were performed to evaluate the therapeutic potential of these cells. <h3>Results</h3> Lung grafts from spontaneously tolerant rats exhibited significantly increased frequencies of MHC-II compared with acutely rejected grafts (13.9 ± 0.9% vs 3.5 ± 0.5%, <i>P</i> < .001). Confocal microscopy assay enhanced presence of MHC-II⁺CD8⁺CD45RC^lowTregs may be attributed to a specialized trogocytosis interaction between CD8⁺CD45RC^lowTregs and pDCs, which facilitated the transfer and chimerism of MHC-II molecules on the surfaces of both CD8⁺CD45RC^lowTregs and pDCs as well. Intervention with IFN-γ resulted in an increased production of MHC-II⁺CD8⁺CD45RC^lowTregs during mixed lymphocyte reactions (<i>P</i> < .01). Conversely, blockade of IDO with anti−IFN-γ antibody or 1-MT significantly decreased the expression (<i>P</i> < .001). MHC-II⁺CD8⁺CD45RC^lowTregs secreted high levels of IL-10, and the adoptive transfer of MHC-II⁺ trogocytosis Tregs notably prolonged the survival of lung-transplanted rats (40.2 ± 8.1 days vs 9.05 ± 2.3 days). <h3>Conclusions</h3> MHC-II⁺CD8⁺CD45RC^lowTregs mediate lung transplantation transient immune tolerance through the IFN-γ/IDO signaling pathway, providing theoretical support for the development of donor-specific immune tolerance clinical strategies.