Maria-Luisa Alegre, United States

My laboratory is interested in T cell responses in settings of transplantation, autoimmunity and cancer, with an emphasis on mouse models and emerging extensions onto clinical translation. A main focus of the laboratory is on T cell tolerance in transplantation and how infections and inflammatory events can affect induction or maintenance of tolerance. We have found that late infections, inflammation or Treg depletion can all erode or break tolerance after it has been successfully established, revealing vulnerabilities to the stability of transplantation tolerance. Preliminary data indicate that in transplantation tolerance, alloreactive T cells specific for donor antigens persistently expressed in the graft become more profoundly dysfunctional than alloreactive T cells specific for transiently expressed graft antigens. We show that infections can reactivate the transient antigen-reactive but not the persistent antigen-reactive T cells to drive rejection, whereas Treg depletion can also re-invigorate the more dysfunctional T cells specific to persistent donor antigens. In this proposal, we will compare the fates of alloreactive T cells of these distinct specificities during tolerance and following infection, inflammation and Treg depletion.

The impact of bacterial infections on transplant outcomes has led us to discover that the microbiota also influences immune responses to transplanted organs and can be manipulated to prolong graft survival. Similarly, we have shown that environmental factors that influence the microbiota composition, such as obesity and exercise, also affect the immune responses against transplanted organs and the kinetics of transplant rejection. Our clinical studies have focused on the immunology of transplant recipients and of patients infected with the bacteria that influence transplant outcomes and, collaboratively, we have explored the involvement of the microbiota in the responsiveness of melanoma patients to immunotherapy.