Tracking of TCR-Transgenic T Cells Reveals That Multiple Mechanisms Maintain Cardiac Transplant Tolerance in Mice.
Solid organ transplantation tolerance can be achieved following select transient immunosuppressive regimens that result in long-lasting restraint of alloimmunity without affecting responses to other antigens. Transplantation tolerance has been observed in animal models following costimulation or coreceptor blockade therapies, and in a subset of patients through induction protocols that include donor bone marrow transplantation, or following withdrawal of immunosuppression. Previous data from our lab and others have shown that proinflammatory interventions that successfully prevent the induction of transplantation tolerance in mice often fail to break tolerance once it has been stably established. This suggests that established tolerance acquires resilience to proinflammatory insults, and prompted us to investigate the mechanisms that maintain a stable state of robust tolerance. Our results demonstrate that only a triple intervention of depleting CD25+regulatory T cells (Tregs), blocking programmed death ligand-1 (PD-L1) signals, and transferring low numbers of alloreactive T cells was sufficient to break established tolerance. We infer from these observations that Tregs and PD-1/PD-L1 signals cooperate to preserve a low alloreactive T cell frequency to maintain tolerance. Thus, therapeutic protocols designed to induce multiple parallel mechanisms of peripheral tolerance may be necessary to achieve robust transplantation tolerance capable of maintaining one allograft for life in the clinic.
Section of Rheumatology, Department of Medicine, The University of Chicago, Chicago, IL.
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ML
Miller
Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.|Department of Biological Sciences, Chicago State University, Chicago, IL.
M D
MD
Daniels
Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.|Department of General Surgery, Division II, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China.
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T
Wang
Section of Rheumatology, Department of Medicine, The University of Chicago, Chicago, IL.
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Y
Wang
Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
J
J
Xu
Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
D
D
Yin
Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
A S
AS
Chong
Section of Rheumatology, Department of Medicine, The University of Chicago, Chicago, IL.
M-L
ML
Alegre
D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D060890:B7-H1 Antigen / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*
D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D011948:Receptors, Antigen, T-Cell
T cell biology; animal models: murine; basic (laboratory) research/science; heart transplantation/cardiology; immunobiology; tolerance: costimulation blockade; tolerance: mechanisms