Pharmacotherapy: concepts of pathogenesis and emerging treatments. Co-stimulation and T cells as therapeutic targets

Abstract

Full activation and differentiation of resting T cells into effector T cells requires at least two signals, the first through engagement of the T cell antigen receptor (TCR) by the antigen-major histocompatibility complex (MHC) on antigen-presenting cells (APCs), and the second by engagement of co-stimulatory molecules such as CD28, on T cells by ligands such as CD80/86 on APCs. Effector T cell differentiation is associated with proliferation, secretion of cytokines and expression of additional surface molecules. These inducible structures may have stimulatory (ICOS, OX40 and 4-1BB) or inhibitory (cytotoxic T-lymphocyte antigen (CTLA)-4) potential. To the extent that T cells have a role in particular immune-mediated diseases, interruption of T cell co-stimulation is a potentially worthwhile approach to the treatment of those conditions. This article summarises the experience in treating rheumatological disease by perturbation of T cell co-stimulation, and also describes structures that could be future targets for this type of therapeutic approach.

Figure 1

Co-stimulatory receptor-ligand pairs present on T cells and antigen presenting cells. On the T cell CD4, CD2, CD5, CD28, CD11a-CD18, CD49d-CD29/CD49d-β7 and CD27 are constitutively expressed. CTLA-4, OX40, ICOS, 4-1BB, CD40L (CD154) and CD97 are upregulated on the T cell surface following activation via the T cell receptor.