Exhaustive Differentiation of Alloreactive CD8+ T Cells: Critical for Determination of Graft Acceptance or Rejection

  title={Exhaustive Differentiation of Alloreactive CD8+ T Cells: Critical for Determination of Graft Acceptance or Rejection},
  author={Ulrich Steger and Christian Denecke and Birgit Sawitzki and Mahzuz Karim and Nick D. Jones and Kathryn J. Wood},
Background. The precise role that CD8+ T cells play in the rejection and acceptance of different types of allograft is unclear and has been shown to vary between donor–recipient combinations. Methods. The response of adoptively transferred CD8+ T cells reactive to the donor alloantigen H2Kb was examined after transplantation of H2Kb+ liver, kidney, and heart grafts in mice. Results. After transfer of 6×106 alloreactive CD8+ T cells to T-cell depleted syngeneic mice spontaneous long-term… 
Differential migration of passenger leukocytes and rapid deletion of naive alloreactive CD8 T cells after mouse liver transplantation
  • Szun S. Tay, B. Lu, P. Bertolino
  • Biology, Medicine
    Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
  • 2013
A mouse liver transplant model is developed in which PLs, recipient cells, and a reporter population of transgenic CD8 T cells specific for the graft could be easily distinguished and quantified in allografts and recipient organs by flow cytometry and shows that alloreactive CD9 T cells are deleted more rapidly than initially reported.
Increased Numbers of Circulating CD8 Effector Memory T Cells before Transplantation Enhance the Risk of Acute Rejection in Lung Transplant Recipients
The measurement of peripheral blood CD8+ effector memory T cells prior to lung transplant may define patients at high risk of acute lung rejection, and suggest a correlation between acute rejection and effectorMemory T cells in lung transplant recipients.
Unique aspects of rejection and tolerance in liver transplantation.
The low incidence of hyperacute or antibody-mediated rejection in liver might be linked to the infrequency of chronic rejection of liver transplants and the availability of better immune monitoring could help develop strategies to recognize tolerance and reduce rejection.
T-cell Exhaustion in Organ Transplantation
Harnessing or encouraging the natural processes of exhaustion may provide a novel strategy to promote graft survival and transplantation tolerance.
Deletion of donor-reactive T cell clones following human liver transplantation
The results suggest that partial deletion of donor-reactive T cell clones may be a consequence of liver transplantation and does not correlate with success or failure of early immunosuppression withdrawal, demonstrating an impact of the liver allograft after accounting for repertoire turnover.
The Role of Diverse Liver Cells in Liver Transplantation Tolerance
The current evidence implicating the tolerogenic properties of diverse liver cells in liver transplantation tolerance is reviewed and proposed liver tolerance mechanisms, such as soluble donor MHC class I molecules, passenger leukocytes theory and a high-load antigen effect are addressed.
Immune Exhaustion and Transplantation
  • A. Sánchez‐Fueyo, J. Markmann
  • Medicine, Biology
    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
  • 2016
Harnessing or encouraging the natural processes of exhaustion may provide a novel means to promote graft survival and transplantation tolerance and the extent of T cell exhaustion occurring with various allografts remains a fertile area for investigation.
Gene Therapy for Tolerance: High-Level Expression of Donor Major Histocompatibility Complex in the Liver Overcomes Naive and Memory Alloresponses to Skin Grafts
High-level expression of donor major histocompatibility complex in recipient livers promotes tolerance to skin allografts, even in animals primed to produce a memory response, providing proof of concept for an approach using liver-targeted gene delivery for tolerance induction to donor antigen.


T-cell activation, proliferation, and memory after cardiac transplantation in vivo.
These data show that the activation of alloantigen-specific T cells can be followed in vivo in short-term and long-term experiments, thereby providing a unique opportunity to study the mechanisms by which T cells respond to allografts in vivo.
Apoptosis within spontaneously accepted mouse liver allografts: evidence for deletion of cytotoxic T cells and implications for tolerance induction.
Observations suggest that T cell deletion, not regulation, may be responsible for spontaneous liver allograft acceptance and the molecular recognition events that cause apoptosis of infiltrating T cells and why this occurs within liver grafts, but not heart or skin grafts remain to be elucidated.
Tolerance to rat liver allografts. III. Donor cell migration and tolerance-associated cytokine production in peripheral lymphoid tissues.
Superinduction of IL-2 and IFN-gamma was, therefore, more closely associated with TOL than was donor cell migration, and this finding has implications for treatment of human liver transplants and is evidence for a novel pathway of transplant tolerance.
Evidence that apoptosis of activated T cells occurs in spontaneous tolerance of liver allografts and is blocked by manipulations which break tolerance.
Findings suggest that a mechanism akin to activation-induced cell death, with apoptosis of alloreactive recipient cells may be responsible for the induction of spontaneous liver transplant tolerance.
Tolerance to rat liver allografts: IV. Acceptance depends on the quantity of donor tissue and on donor leukocytes.
It is shown that spontaneous acceptance is reconstituted by intravenous injection of donor leukocytes, and it appears likely that spontaneous liver transplant tolerance is a high-dose or activation-associated immune phenomenon.
The results suggest that liver transplantation induces donor-specific tolerance in vivo, which may not be reflected in in vitro proliferative and cytotoxicity assays (split tolerance).
Differential Susceptibility of Heart, Skin, and Islet Allografts to T Cell-Mediated Rejection1
Evidence is provided that neither tissue-specific Ags nor, surprisingly, the number of APCs carried in the graft dictate their susceptibility to T cell-mediated rejection and that the graft microenvironment and size may play a more important role in determining the susceptibility of an allograft to rejection and resistance to tolerance induction.
CD40 ligand blockade induces CD4+ T cell tolerance and linked suppression.
It is shown here that CD4+ T cells rendered tolerant using anti-CD40L therapy exhibit the same regulatory property of linked suppression, as demonstrated by their ability to accept grafts expressing third party Ags only if they are expressed in conjunction with the tolerated Ags.
Complete differentiation of CD8+ T cells activated locally within the transplanted liver
It is concluded that local antigen presentation cannot explain liver tolerance and, on the contrary, the liver may be an excellent priming site for naive CD8+ T cells.
Murine Renal Allografts: Spontaneous Acceptance Is Associated with Regulated T Cell-Mediated Immunity1
Transplanted DBA/2 kidneys into nephrectomized C57BL/6 mice, and the allografts were spontaneously accepted for >60 days without immunosuppression, suggesting a donor-reactive, cell-mediated immune mechanism involving TGF-β is associated with the spontaneous acceptance of renal allografteds in mice.