Allograft rejection is characterized by effector CD4+ T cell activation in response to donor antigen and an intense cellular and humoral attack on the graft. Furthermore, multiple intracellular signals within CD4+ T cells operate co-incidentally to enhance the expansion and function of regulatory CD4+Foxp3+ T cell subsets that collectively serve to control the alloimmune response. In addition, the potency of this process of immunoregulation prevents and restrains alloimmune T effector cell activation and rejection. Importantly, recent advances indicate that CD4+Foxp3+ T cell differentiation and function are negatively regulated by the cell intrinsic activity of mTOR and specifically mTORC1. However, little is known about the regulation of intracellular mTOR signaling within alloreactive CD4+ T cell effectors, or how its relative activity may be modulated in Foxp3+ subsets, or whether it is possible to exploit modulatory signals to augment physiological Treg activity in pathological states to prevent disease, including the development of chronic allograft rejection. DEPTOR is a recently discovered cell intrinsic factor that modulates mTOR-induced signaling responses in highly proliferative cancer cells, and we have observed that it regulates the activation of normal cell types including vascular endothelial cells and CD4+ T cells. The expression of DEPTOR is reduced upon activation, suggesting that sustained expression will have immunomodulatory effects. Our objectives in this R01 are to further evaluate these observations using novel transgenic mice, and 1), define the select function of DEPTOR in CD4+ T effector and regulatory subsets, 2), evaluate the consequences of CD4+ T cell DEPTOR expression in models of transplant rejection; and 3), evaluate whether intragraft expression of DEPTOR serves to augment local Treg activity and long term graft survival. We will test the hypotheses that: a) DEPTOR is a cell intrinsic molecule that augments CD4+ T regulatory cell function and modulates CD4+ T effector cell activation to enhance immunoregulation, and b) that cell intrinsic expression of DEPTOR augments the immunoregulatory phenotype of EC and EC-dependent interactions with CD4+ Tregs to promote long-term graft survival. We propose three specific aims in which we will determine: 1), the consequences and mechanism of function of cell intrinsic DEPTOR in CD4+ T cell subsets, 2), the function of CD4+ T cell DEPTOR in long-term allograft survival; and 3), the association between endothelial cell expression of DEPTOR and local Treg activity, intragraft immunoregulation and long-term graft survival. Collectively, these innovative studies will have broad scientific and biological implications of great significance and relevance to transplantation immunobiology.
Organ transplantation is a life saving therapy for individuals with end stage organ failure, but all transplants eventually fail due to a process called chronic allograft rejection. In this research proposal, we plan to determine if a recently discovered cell intrinsic regulatory protein, called DEPTOR, functions in CD4+ T cells and endothelial cells of the donor allograft to modulate the alloimmune response and rejection. We will also evaluate if pharmacological manipulation of DEPTOR expression augments immunoregulation, prevents chronic rejection and prolongs graft survival.
| Caron, Alexandre; Briscoe, David M; Richard, Denis et al. (2018) DEPTOR at the Nexus of Cancer, Metabolism, and Immunity. Physiol Rev 98:1765-1803 |
