The FDA approval of belatacept has thus spurred desire for developing a clinically translatable strategy to inhibit the CD154 and CD40 pathway in order to harness this synergy to achieve maximum benefit in clinical application

The FDA approval of belatacept has thus spurred desire for developing a clinically translatable strategy to inhibit the CD154 and CD40 pathway in order to harness this synergy to achieve maximum benefit in clinical application. decade has resulted in substantial evidence that the ultimate end result of T-cell tolerance versus immunity is usually critically regulated by the match of co-stimulatory and co-inhibitory signals received during T-cell activation. These second signals serve to fine-tune the T-cell response, both in terms of its magnitude and the appropriateness of the response, based on the context of antigen presentation. The CD28 (T-cell-specific surface glycoprotein CD28) and CTLA-4 (cytotoxic T-lymphocyte protein 4) pathways were first implicated in tipping the balance between T-cell activation or anergy (whereby the immune system cannot elicit a response), although mounting evidence over the past few years has revealed a number of other co-stimulatory pathways that serve to shape the immunological response further. In this Review, we discuss the crucial interactions in the provision of T-cell co-stimulation and the functional importance of these interactions in transplantation, tolerance, and autoimmunity. We also describe how therapeutic blockade of these pathways might be harnessed to manipulate the immune response to prevent or attenuate pathological responses. The immunoglobulin superfamily [H1] The CD28, CTLA-4, CD80 and CD86 pathways Balancing signals: mechanistic insights The best studied pathways of the immunoglobulin superfamily are the CD28 and CTLA-4, and the CD80 (T-lymphocyte activation antigen CD80) and CD86 (T-lymphocyte activation antigen CD86) pathways.1,2 CD80 and CD86 are expressed on the surface of antigen presenting cells (APCs) and NGP-555 modulate the activity of responding CD4+ and NGP-555 CD8+ T cells by alternatively binding to the CD28 co-stimulator, which is constitutively expressed on the surface of naive and activated T cells, or the CTLA-4 co-inhibitor, AKAP10 which is inducibly expressed on both CD4+ and CD8+ T cells upon activation (Determine 1). Seminal studies in the NGP-555 early 1990s explained the therapeutic blockade of this pathway using an immunoglobulin (Ig) fusion protein, CTLA-4-Ig (abatacept), which binds to CD80 and CD86 and thereby blocks both activating CD28 signals and inhibitory CTLA-4 signals,1,3 in models of transplantation and autoimmunity.3C6 Data from a myriad of studies in the ensuing years revealed further mechanistic insights regarding the effect of CD28 and CTLA-4 blockade on antigen-specific T-cell responses. For example, cell death pathways were shown to be critically involved in T-cell tolerance induced by CD28 and CTLA-4 blockade. 7 CD28 and CTLA-4 blockade effectively inhibits na?ve antigen-specific CD4+ T-cell responses,8,9 but incompletely controls the growth of antigen-specific CD8+ T-cell responses.8 In addition, CD8+ memory T-cell responses in both murine and nonhuman primate models are, in most cases, independent of the CD28 pathway during recall immunity10C13 Initial studies using total CD4+ T cells to study CD4+ memory T-cell responses indicated that these cells were effectively attenuated after CTLA-4-Ig administration,10,14 but subsequent in-depth analysis of the effect of co-stimulation blockade on individual CD4+ helper T-cell subsets has suggested a resistance of IL-17 secreting CCR6+ memory type 17 T helper cells (TH17) cells to CD28 and CTLA-4 blockade.15 Furthermore, the initial antigen-specific T-cell precursor frequency was shown to be an important factor in determining the effectiveness of CD28 and CTLA-4 blockade in a murine model of transplantation,16 suggesting that patients with an initially high precursor frequency of autoreactive or alloreactive T cells (as is often the case with poor major histocompatibility complex donor and recipient matching), might be particularly refractory to treatment with CD28 and CTLA-4 blockade. Open in NGP-555 a separate window Physique 1 Complexities of the CD28 co-stimulatory pathwayThe CD28 co-stimulatory receptor can be ligated by CD80, CD86, and ICOS-L (B7-H2). The CTLA-4 co-inhibitor competes with CD28 for binding to CD80 and CD86. However, CD80 can also bind to PD-L1 (B7-H1) and deliver a co-inhibitory transmission. ICOS competes with CD28 for binding to B7-H2. Abbreviations: B7-H1, programmed cell death 1 ligand 1; B7-H2, NGP-555 ICOS ligand; CD28, T-cell-specific surface glycoprotein CD28; CD80, T-lymphocyte activation antigen CD80; CD86, T-lymphocyte activation antigen CD86; CTLA-4, cytotoxic T-lymphocyte protein 4; ICOS, inducible T-cell costimulator; PD-L1,.