T-cell co-stimulatory pathways in autoimmunity

Abstract

T-cell activation and differentiation depend on the signal strength received by the T-cell receptor and on signals provided by co-stimulatory molecules. The most prominent co-stimulatory molecule is CD28, which controls the activation of naïve and memory T cells by antigen presented on professional antigen-presenting cells. Blocking of the CD28-CD80/86 pathway has been an appealing strategy for inducing tolerance in autoimmune diseases where the disease-inducing autoantigens are not known. Although CD28 has maintained its unique position, the past decade has witnessed the recognition that a large number of regulatory molecules on T cells must be stimulated to generate a fully protective immune response. These regulatory receptors differ in their preferential expression on T-cell subsets, in the ligands that they recognize, and in the signaling pathways that they trigger. They have in common the fact that they provide information on the cellular environment in which the T-cell response occurs. By intercepting these signals, we may be able to influence disease-relevant T-cell responses in autoimmune diseases while potentially minimizing broad immunosuppression.

Figure 1

Co-stimulatory receptor-ligand pairs in the initiation of a T-cell response. CD27 and CD28 are co-stimulatory molecules that are constitutively expressed. Their ligands CD70, CD80, and CD86 are inducible on dendritic cells upon their activation. The CD154-CD40 interaction represents an important amplification loop that upregulates the expression of CD80 and CD86. MHC, major histocompatibility complex; TCR, T-cell receptor.

Figure 2

Activation-induced co-stimulatory receptors and their ligands. Upon activation, T cells express a number of receptors that have co-stimulatory ability and are important for sustained activation, proliferation, and differentiation. Their ligands again are expressed on antigen-presenting cells. ICOS, inducible co-stimulator; MHC, major histocompatibility complex; TCR, T-cell receptor.

Figure 3

Co-stimulatory receptor-ligand pairs in the synovium. Effector T-cell populations frequently lose the expression of CD27 and CD28 and gain the expression of regulatory receptors that bind to ligands in the synovium. In general, these receptors as well as their ligands are constitutively expressed independent of cell activation. CD47 is expressed on all T cells irrespective of their differentiation status and receives a co-stimulatory signal from a trimolecular complex formation including CD36 on synoviocytes or endothelial cells and thrombospondin produced in the synovial tissue. KIR, killer immunoglobulin-like receptor; MHC, major histocompatibility complex; TCR, T-cell receptor.