CD28 and CD80/CD86 Pathway

Introduction

CD28 is one of the most important costimulatory molecules expressed by naive and primed T cells and is essential for full T cell activation and the development and homeostasis of Treg cells. CD80 (B7-1) and CD86 (B7-2) represent the two structurally homologous ligands of CD28, which are expressed by antigen-presenting cells (APCs), including dendritic cells (DCs). Expression of each ligand is upregulated by infection, tissue injury, or the production of inflammatory cytokines or after the contact of APCs with activated T cells. CD86 seems likely to play a more critical role in providing early and sustained costimulatory signals, whereas CD80-derived signals modulate the fate of the T cell response rather than its initiation. CTLA-4 is homologous to CD28 and binds CD80-CD86 with a much higher affinity than CD28. Consequently, CD28 competes with CTLA-4 to bind CD80 and CD86, resulting in enhanced T-cell responses by up-regulating cytokine secretion and inducing cell proliferation.

Preclinical and Clinical Development of Drugs for CD28 and CD80/CD86 Pathway

Cancers

The CD28-CD80/CD86 costimulatory pathway plays a critical role in T cell activation and is implicated in the prognosis of cancers and their response to immunotherapies. Expression of CD28, CD80, and/or CD86 may therefore serve as clinically significant prognostic biomarkers.

Autoimmune diseases

More recently, there has been a renewed interest in developing CD28-specific therapies. Antagonist-only anti-CD28 antibodies that have modulated Fc or conjugated with polyethylene glycol have been developed. These antibodies have been tested in animal models of psoriasis, arthritis, autoimmune uveitis, and SLE nephritis. Some compounds seem to be highly effective in preclinical transplantation models and autoimmunity, presumably because they preserve coinhibitory signals transmitted through CTLA-4. Importantly, selective CD28 blockade better preserves Treg functionality and better inhibits pathogenic memory T cell responses in transplantation relative to CTLA-4-Ig. Thus, selective CD28 targeting may have clinical benefits for many autoimmune diseases.

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