Resilience of T cell-intrinsic dysfunction in transplantation tolerance

Proc Natl Acad Sci U S A. 2019 Nov 19;116(47):23682-23690. doi: 10.1073/pnas.1910298116. Epub 2019 Nov 4.


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.

Keywords: T cells; exhaustion; memory; tolerance; transplantation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / transplantation
  • Forkhead Transcription Factors / analysis
  • Genes, Reporter
  • Graft Rejection / immunology
  • Graft Survival / immunology*
  • H-2 Antigens / immunology
  • Heart Transplantation
  • Histocompatibility Antigens Class II / immunology
  • Immune Tolerance / immunology*
  • Immunologic Memory
  • Isoantigens / immunology
  • Listeria monocytogenes
  • Listeriosis / immunology
  • Lymphocyte Transfusion
  • Mice
  • Mice, Congenic
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Postoperative Complications / immunology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Regulatory / immunology
  • Tissue Donors
  • Transplantation Immunology*


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • H-2 Antigens
  • H-2K(K) antigen
  • Histocompatibility Antigens Class II
  • I-A(b) antigen, mouse
  • Isoantigens