Negative T cell costimulation and islet tolerance.
Activation of self-reactive T cells that specifically destroy the pancreatic beta-cells is one of the hallmarks in the development of type 1 diabetes. Thus, for prevention and treatment of this autoimmune disease, approaches to induce and maintain T cell tolerance toward the beta-cells, especially in islet transplantation, have been actively pursued. Noticeably, many of the recent protocols for inducing transplant tolerance involve blockade of positive T cell costimulation extrinsically. Though highly effective in prolonging graft survival, these strategies alone might not be universally sufficient to achieve true tolerance. As the mystery of the suppressive and regulatory T cells unfolds, it is becoming appreciated that exploiting the intrinsic molecular and cellular mechanisms that turn off an immune response would perhaps facilitate the current protocols in establishing T cell tolerance. In this perspective, here we summarize the recent findings on the negative costimulation pathways, in particular, the newly identified PD-1 : PD-L interactions. On the basis of these observations, we propose a new principle of curtailing pathogenic T cell response in which blockade of positive T cell costimulation is reinforced by concurrent engagement of the negative costimulation machinery. Such a strategy may hold greater hope for therapeutic intervention of transplant rejection and autoimmune diseases.
Gao
Wenda
W
Department of Medicine, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, Boston, MA 02215, USA. wgao@caregroup.harvard.edu
Demirci
Gülçin
G
Li
Xian Chang
XC
D003922:Diabetes Mellitus, Type 1 / Q000601:surgery*; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D018448:Models, Immunological; D013601:T-Lymphocytes / Q000276:immunology*