Inducible T-cell costimulatory (ICOS), also known as CD278, is a costimulatory receptor mainly expressed on activated T lymphocytes. ICOS is the third member of the CD28 family of co-receptor molecules, showing significant homology to the CD28 (a co-stimulatory immunoreceptor constitutively expressed on naïve T cells). Generally, ICOS present on the activated CD4 and CD8 T cell surface as a glycosylated disulfide-linked homodimer with an extracellular IgV domain and an FDPPPF motif for the binding of the ligand. B7-related peptide 1 (B7RP1) is the unique ligand for ICOS, also known as ICOSL and CD275, presenting on B cells, antigen-presenting cells, and macrophages. B7RP1 is a B7-related transmembrane glycoprotein with two extracellular domains: IgV and IgC.
When the T cell receptor (TCR) recognized foreign antigens, the T cells were activated, thereby ICOS expression was induced. Meanwhile, the B7RP1 expression is quickly upregulated by inflammatory cytokines. B7RP1 binding to ICOS activates signaling pathways and provides a costimulatory signal for T cells, promoting T-cell activation, differentiation, cytokine secretion, immune memory, and enhancing the reactivity of T cells to antigens.
Fig.1 Model of ICOS-mediated Tfh cell differentiation. (Wikenheiser, 2016)
There is immune homeostasis in the human body, which mediates an immune response to exogenous or abnormal substances and has an immune tolerance to autologous substances. The disruption of immune homeostasis and self-tolerance leads to autoimmunity, causing inflammation and autoimmune diseases mediated by autoreactive T cells and autoantibodies. The ICOS-B7RP1 co-stimulatory pathway plays a significant role in T cell autoimmunity and a variety of autoimmune diseases. And targeting ICOS/ICOSL could represent a plausible approach to new therapy development for autoimmune disease treatment.
Myasthenia Gravis is a neurological autoimmune disease caused by autoantibodies block nicotinic acetylcholine receptors at the neuromuscular junction, impairing nerve impulses for triggering muscle contractions. It has been demonstrated that ICOS knockout mice had a lower level of serum acetylcholine receptor antibody and showed high resistance to experimental autoimmune myasthenia gravis development. And ICOS deficiency suppressed the proliferation of lymphocytes and the differentiation of Th1 and Th2 cells.
It has been detected that ICOS expression on CD4 and CD8 T cells among synovial fluid mononuclear cells was significantly higher than that among peripheral blood mononuclear cells, and with increased production of IFN-γ, IL-4, and IL-10 by synovial fluid CD4 T cells. And the B7RP1mRNA levels in synovial tissue of RA patients were also elevated. Moreover, blocking the ICOS-B7RP1 pathway anti-B7h monoclonal antibody notably ameliorated collagen-induced arthritis in mice.
Compared with healthy subjects, SLE patients had increased expressions of ICOS on both CD4 and CD8T cells but decreased expressions of B7RP1 on the peripheral blood memory B cells. And ICOS-B7RP1 signaling remarkably enhanced the production of anti-dsDNA autoantibodies in SLE patients, playing an immune-pathogenetic role in SLE.
The critical role of ICOS-B7RP1 mediated co-stimulation in sustaining T-cell activation and effector functions pulls it an important factor in the pathogenesis of an array of autoimmune diseases, such as type 1 diabetes mellitus, multiple sclerosis, and myositis. And ICOS-B7RP1 signaling exhibits great therapeutic potential for treating autoimmune diseases.
Fig.2 Multiple roles of ICOS on immune function. (Sakthivel, 2009)
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