Resident memory T cells form during persistent antigen exposure leading to allograft rejection

Recipient effector T cells differentiate into functional tissue-resident memory T cells, causing graft rejection after kidney transplantation. Memories of rejection Long-term graft survival after organ transplantation can be hindered by immune-mediated allograft rejection; thus, understanding these immune responses is crucial to developing new transplant-supporting therapies. Tissue-resident memory T cells (TRM), a subset of memory T cells that reside in barrier tissues and do not recirculate, are detectable in transplanted organs, but it is unclear if they contribute to allograft rejection. Abou-Daya et al. created a mouse model of T cell–mediated kidney transplant rejection, showing that adoptively transferred, kidney antigen–specific effector T cells differentiated into functional, nonrecirculating antigen-specific TRM in the transplanted kidneys. These kidney antigen–specific TRM induced allograft rejection. These data suggest that TRM in transplanted allografts can contribute to rejection and that targeting alloreactive TRM might improve long-term graft survival in transplant recipients. Tissue-resident memory T cells (TRM) contained at sites of previous infection provide local protection against reinfection. Whether they form and function in organ transplants where cognate antigen persists is unclear. This is a key question in transplantation as T cells are detected long term in allografts, but it is not known whether they are exhausted or are functional memory T cells. Using a mouse model of kidney transplantation, we showed that antigen-specific and polyclonal effector T cells differentiated in the graft into TRM and subsequently caused allograft rejection. TRM identity was established by surface phenotype, transcriptional profile, and inability to recirculate in parabiosis and retransplantation experiments. Graft TRM proliferated locally, produced interferon-γ upon restimulation, and their in vivo depletion attenuated rejection. The vast majority of antigen-specific and polyclonal TRM lacked phenotypic and transcriptional exhaustion markers. Single-cell analysis of graft T cells early and late after transplantation identified a transcriptional program associated with transition to the tissue-resident state that could serve as a platform for the discovery of therapeutic targets. Thus, recipient effector T cells differentiate into functional graft TRM that maintain rejection locally. Targeting these TRM could improve renal transplant outcomes.