Related Experiment Videos
Cutting edge: perforin down-regulates CD4 and CD8 T cell-mediated immune responses to a transplanted organ
Anirban Bose1, Yoshihiko Inoue, Kenneth E Kokko
1Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Abstract:
Perforin mediates target cell apoptosis by CTLs and NK cells. Although perforin expression correlates strongly with acute allograft rejection, perforin-deficient mice reject allografts with the same kinetics as wild-type recipients. In this study, we tested the hypothesis that while perforin is dispensable for acute rejection, it is essential for down-regulating the alloimmune response by inducing the apoptosis of host immune cells. Using a skin transplantation model, we found that perforin-deficient mice are resistant to the induction of allograft acceptance by agents that block T cell costimulation. Failure to induce allograft acceptance in these mice was observed irrespective of whether the alloimmune response was CD4 or CD8 T cell-mediated and could be attributed to defective apoptosis of activated CD4 and CD8 T cells. In contrast, perforin did not influence T cell proliferation. Therefore, perforin is an essential immunoregulatory molecule that may be required for the induction of transplantation tolerance.
Insights
Perforin is not essential for acute allograft rejection but is crucial for down-regulating immune responses. Perforin deficiency impairs the induction of transplantation tolerance by hindering T cell apoptosis.
Area of Science:
- Immunology
- Transplantation Biology
- Cellular Biology
Background:
- Perforin is a key mediator of apoptosis induced by cytotoxic T lymphocytes (CTLs) and NK cells.
- While perforin expression correlates with acute allograft rejection, its absence does not alter rejection kinetics in mice.
- The role of perforin in regulating the alloimmune response and inducing transplantation tolerance remains unclear.
Purpose of the Study:
- To investigate the role of perforin in down-regulating alloimmune responses and inducing transplantation tolerance.
- To test the hypothesis that perforin is essential for inducing apoptosis of host immune cells, thereby regulating the immune response.
Main Methods:
- Utilized a skin transplantation model in perforin-deficient and wild-type mice.
- Administered agents that block T cell costimulation to assess the induction of allograft acceptance.
- Analyzed CD4 and CD8 T cell apoptosis and proliferation in response to allografts.
Main Results:
- Perforin-deficient mice were resistant to the induction of allograft acceptance via costimulation blockade.
- This resistance was observed regardless of whether the alloimmune response was CD4 or CD8 T cell-mediated.
- Defective apoptosis of activated CD4 and CD8 T cells was identified as the cause of impaired tolerance induction in perforin-deficient mice.
- Perforin did not significantly affect T cell proliferation.
Conclusions:
- Perforin is dispensable for acute allograft rejection but essential for regulating the alloimmune response.
- Perforin plays a critical role in inducing the apoptosis of activated T cells, which is necessary for transplantation tolerance.
- Perforin is an essential immunoregulatory molecule required for inducing transplantation tolerance.