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

Abstract

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.

Reprogramming Alveolar Macrophage Responses to TGF-β Reveals CCR2+ Monocyte Activity that Promotes Bronchiolitis Obliterans Syndrome

“…Viral peptide-and alloantigen-specific T RM can become reactivated upon cognate antigen encounter ( 28, 57 ). We next isolated PD-1 + CD49a + CD8 + T cells from 3T-FVB allografts with BOS and measured IFN-γ expression in response to stimulation with 3T-FVB allograft-derived Mo-AM and TR-AM ( Fig.…”

Human lung tissue resident memory T cells are re-programmed but not eradicated with systemic glucocorticoids after acute cellular rejection

“…Importantly, this accumulation of recipient derived T cells in the allograft occurred faster in the setting of ACR 11 . In a murine model of delayed rejection after orthotopic renal transplantation, polyclonal, antigen-specific CD8 + T RM populated the graft, and contributed to the development of chronic rejection 24 . Furthermore, renal allografts after human transplantation contained CD8 + T RM that could produce large amounts of granzyme B, perforin, IFNγ, and TNFα after stimulation with the phorbol ester, PMA/Ionomycin 25 .…”

Transplantation and Re-transplantation of Mouse Kidney Grafts to Study Local Immune Responses

“…Furthermore, the rejection of a mouse kidney allograft is slow 37 . This makes mouse kidney allograft re-transplantation a better model to study local immune responses, which need su cient time to be established after transplantation 19 . The purpose of this protocol is to provide repeatable stepwise procedures for mouse kidney re-transplantation.…”

“…Since the rst mouse kidney transplantation experimental model was established in 1973 3 , the techniques have been re ned and new techniques were developed to improve the survival rate of recipients 4,5,6,7,8,9,10,11,12,13,14 . In our lab, we continued to improve and utilize this model to study innate and adaptive mechanisms of rejection 15,16,17,18,19,20 . In the past three decades, signi cant advances have been made in prevention of acute graft rejection and improving early graft survival.…”

“…Till date, mouse kidney allograft re-transplantation has not been reported primarily due to di culties in the secondary revascularization of the graft, re-establishment of the urinary tract continuity, and dissecting extensive adhesions during harvesting a transplanted kidney and ureter. We recently successfully established a mouse kidney re-transplantation model to investigate the role of T RM in kidney allograft rejection 19 . This detailed stepwise protocol will be of great value to nephrologists, immunologists, transplantation scientists, and microsurgeons interested in studying the local immune response.…”