Chapter 11 - T-Cell Costimulation and Coinhibition in Graft-Versus-Host Disease and Graft-Versus-Leukemia Effect

Abstract

The central effect of graft-versus-host disease (GVHD) development and graft-versus-leukemia (GVL) lies in T-cell activation, proliferation, and differentiation after allogeneic hematopoietic cell transplantation (HCT). It is a well-established concept that a productive T-cell activation requires two signals: T-cell receptor and costimulation. The outcome of T-cell activation is critically regulated by the constellation of costimulatory and coinhibitory receptors expressed on the cell surface. In this article, we review recent progresses in the understanding of T-cell costimulation and coinhibition in allogeneic HCT and consider the therapeutic implications of modulating costimulatory and coinhibitory pathways in the prevention and treatment of GVHD as well as in the maintenance of GVL effect. While the B7:CD28/CTLA-4 pathway is the best-characterized T-cell costimulatory pathway, there are now many additional costimulatory pathways. Besides the expanded B7/CD28 superfamily, the other large group of costimulatory molecules belongs to TNF/TNFR superfamily. In addition, emerging studies have been focusing on how coinhibitory signals through PD-1 and CTLA-4 among other coinhibitory molecules regulate T-cell activation and function. We will focus on the costimulatory and coinhibitory molecules B7/CD28 and TNF/TNFR superfamily members and highlight their roles in regulating the nature of the immune response in consideration of both effector and regulatory T cells in GVHD and GVL effects.