Role of CD8+T Cells Exhaustion in Long Term Spontaneous Acceptance of Mouse Kidney Allograft
1Center of Transplant Science, Massachusetts General Hospital, Boston, MA, 2Department of Pathology, Massachusetts General Hospital, Boston, MA, 3Department of Surgery, Boston Children's Hospital, Boston, MA
Meeting: 2022 American Transplant Congress
Abstract number: 1252
Keywords: Kidney transplantation, T cell graft infiltration, Tolerance
Topic: Basic Science » Basic Science » 10 - Treg/Other Regulatory Cell/Tolerance
Session Information
Session Name: Treg/Other Regulatory Cell/Tolerance
Session Type: Poster Abstract
Date: Monday, June 6, 2022
Session Time: 7:00pm-8:00pm
Presentation Time: 7:00pm-8:00pm
Location: Hynes Halls C & D
*Purpose: CD8+ T cells exhaustion has been shown to promote chronic viral infection and tumor development, resulting from long term exposure to foreign antigen. We hypothesize in the setting of transplantation, graft infiltrating donor reactive CD8+ T cells stimulated by persistent alloantigen acquire an exhaustion phenotype, contributing to graft tolerance. By using an MHC fully-mismatched mouse model for spontaneous acceptance of kidney transplants, we investigated the role of exhausted alloreactive CD8+ T cells and their impact on kidney graft survival.
*Methods: DBA/2j (DBA) mouse kidneys were transplanted into C57BL/6 (B6) or CD8 KO mice. Renal function was assessed by BUN. For Treg depletion, Foxp3-DTR mice on C57BL/6 background were used as recipients and DT was administered intraperitoneally. DBA/2j x OVA F1 donor kidney grafts were transplanted to C57BL/6 recipients followed by OT-I cells adoptive transfer to trace donor specific CD8+ T cells. Graft infiltrating immune cells were analyzed by flow cytometry. Thymectomy was performed by vacuum suction through superior sternum approach.
*Results: B6 recipients spontaneously accepted DBA kidneys without immunosuppression reagents and depletion Treg 6 months after transplant did not affect BUN level. Thymectomized B6 with DBA kidney graft survived over 100 days. CD8+ T cells from DBA kidney allografts expressed higher levels of PD1, TIM-3, Eomes, Tox, and CD39 when compared to splenic CD8 T cells. Moreover, granzyme B and TNF-α production was impaired 12 weeks after transplant. Eomeshi PD1hiOT-I CD8+ cells were not completely deleted by tolerant recipients after adoptive transfer. Anti-PD1 antibody treatment triggered an immune response against DBA kidneys whereas treated CD8 KO recipients did not reject the allografts.
*Conclusions: Here we show that infiltrating donor antigen specific CD8+ T cells are not fully cleared by recipients and develop an exhaustion phenotype. Anti-PD1 antibody treatment, which blocks the maintenance of exhaustion, results in the rejection of the accepted kidney allograft in our model of spontaneous acceptance.
To cite this abstract in AMA style:
Ge J, Szuter E, Yokose T, Rosales I, Cuenca A, Russell P, Madsen J, Colvin R, Alessandrini A. Role of CD8+T Cells Exhaustion in Long Term Spontaneous Acceptance of Mouse Kidney Allograft [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/role-of-cd8t-cells-exhaustion-in-long-term-spontaneous-acceptance-of-mouse-kidney-allograft/. Accessed May 6, 2025.« Back to 2022 American Transplant Congress