Resilience of T cell-intrinsic dysfunction in transplantation tolerance

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 47; pp. 23682 - 23690
• Main Authors: Miller, Michelle L., McIntosh, Christine M., Wang, Ying, Chen, Luqiu, Wang, Peter, Lei, Yuk Man, Daniels, Melvin D., Watkins, Elyse, Solano, Carolina Mora, Chong, Anita S., Alegre, Maria-Luisa
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.11.2019
• Series: PNAS Plus
• Subjects: Allografts; Animals; Antigens; Biological Sciences; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - transplantation; Cell differentiation; Disruption; Disseminated infection; Forkhead Transcription Factors - analysis; Genes, Reporter; Graft Rejection - immunology; Graft Survival - immunology; Grafts; H-2 Antigens - immunology; Heart Transplantation; Heart transplants; Histocompatibility Antigens Class II - immunology; Immune Tolerance - immunology; Immunologic Memory; Immunological memory; Immunological tolerance; Immunosuppression; Isoantigens - immunology; Listeria; Listeria monocytogenes; Listeriosis - immunology; Lymphocyte Transfusion; Lymphocytes; Lymphocytes T; Memory cells; Mice; Mice, Congenic; Mice, Inbred BALB C; Mice, Inbred C57BL; Phenotypes; PNAS Plus; Postoperative Complications - immunology; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - immunology; Tissue Donors; Transfusion; Transplantation; Transplantation Immunology; exhaustion; memory; T cells; tolerance; transplantation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1910298116

Following antigen stimulation, naïve T cells differentiate into memory cells that mediate antigen clearance more efficiently upon repeat encounter. Donor-specific tolerance can be achieved in a subset of transplant recipients, but some of these grafts are rejected after years of stability, often following infections. Whether T cell memory can develop from a tolerant state and whether these formerly tolerant patients develop antidonor memory is not known. Using a mouse model of cardiac transplantation in which donor-specific tolerance is induced with costimulation blockade (CoB) plus donor-specific transfusion (DST), we have previously shown that systemic infection with Listeria monocytogenes (Lm) months after transplantation can erode or transiently abrogate established tolerance. In this study, we tracked donor-reactive T cells to investigate whether memory can be induced when alloreactive T cells are activated in the setting of tolerance. We show alloreactive T cells persist after induction of cardiac transplantation tolerance, but fail to acquire a memory phenotype despite becoming antigen experienced. Instead, donor-reactive T cells develop T cell-intrinsic dysfunction evidenced when removed from the tolerant environment. Notably, Lm infection after tolerance did not rescue alloreactive T cell memory differentiation or functionality. CoB and antigen persistence were sufficient together but not separately to achieve alloreactive T cell dysfunction, and conventional immunosuppression could substitute for CoB. Antigen persistence was required, as early but not late surgical allograft removal precluded the acquisition of T cell dysfunction. Our results demonstrate transplant tolerance-associated T cell-intrinsic dysfunction that is resistant to memory development even after Lm-mediated disruption of tolerance.