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.
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.
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.
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.
T-cell exhaustion in allograft rejection and tolerance
Preventing or reversing T-cell exhaustion may lead to prevention of transplant tolerance or triggering of rejection; therefore, caution should be exercised in the use of agents blocking inhibitory receptors for the treatment of chronic viral infections or tumors in transplant recipients.
Liver Transplant Tolerance and Its Application to the Clinic: Can We Exploit the High Dose Effect?
The growing body of evidence is outlined, from experimental models and clinical transplantation, which supports a role for large tissue mass and high antigen dose in the induction of tolerance, and a novel gene therapy approach to exploit this dose effect and induce antigen-specific tolerance robust enough to overcome a primed T cell memory response.
Long-Term Signs of T Cell and Myeloid Cell Activation After Intestinal Transplantation With Cellular Rejections Contributing to Further Increase of CD16+ Cell Subsets
The intestine mediates a delicate balance between tolerogenic and inflammatory immune responses. The continuous pathogen encounter might also augment immune cell responses contributing to
Regulatory T‐cell therapy in liver transplantation
The evidence from drug withdrawal trials of spontaneous operational tolerance in liver transplantation, the unique immunology of the hepatic microenvironment, the evidence for the use of CD4+CD25+FOXP3+ regulatory T cells as a tolerance inducing therapy in liver transplants and the challenges in producing clinical grade Treg cell products are summarized.


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.
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.
CD40-CD40 Ligand-Independent Activation of CD8+ T Cells Can Trigger Allograft Rejection1
It is concluded that CD40L is not an important costimulatory molecule for CD8+ T cell activation and that following transplantation donor APC can activate recipient CD8- T cells directly without first being primed by CD4+ T cells.
Crucial Fas–Fas ligand interaction in spontaneous acceptance of hepatic allografts in mice
It is suggested that the Fas/FasL system plays a critical role for recipient immunoregulation, enabling recipients in accepting hepatic allografts by deletion of the donor‐specific T cells, but not for CTL/target cell interaction in MRL+/+ recipients.