During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.
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T Cell Co-stimulation
T cells require two signals to become fully activated. A first signal, which is antigen-specific, is provided through the T cell receptor or TCR which interacts with peptide-MHC molecules on the membrane of antigen presenting cells (APC). A second signal, the co-stimulatory signal, is antigen nonspecific and is provided by the interaction between co-stimulatory molecules expressed on the membrane of APC and the T cell.
One of the best characterized costimulatory molecules expressed by T cells is CD28, which interacts with CD80 (B7.1) and CD86 (B7.2) on the membrane of APC. Another costimulatory receptor expressed by T cells is ICOS ( Inducible Costimulator), which interacts with ICOS-L.
T cell co-stimulation is necessary for T cell proliferation, differentiation and survival. Activation of T cells without co-stimulation may lead to T cell anergy, T cell deletion or the development of immune tolerance.
B Cell Co-stimulation
B cell binds antigens with its BCR (a membrane-bound antibody), which transfers intracellular signals to the B cell as well as inducing the B cell to engulf the antigen, process it, and present it on the MHC II molecules. The latter case induces recognition by antigen-specific Th2 cells, leading to activation of the B cell through binding of TCR to the MHC-antigen complex. It is followed by synthesis and presentation of CD40L (CD154) on the Th2 cell, which binds to CD40 on the B cell, thus the Th2 cell can co-stimulate the B cell. Without this co-stimulation the B cell cannot proliferate further.
Co-stimulation for B cells is provided alternatively by complement receptors. Microbes may activate the complement system directly and complement component C3b bind to microbes. After C3b is degraded into a fragment iC3b (inactive derivative of C3b), then cleaved to C3dg, and finally to C3d, which continue to bind to microbal surface, B cells express complement receptor CR2 (CD21) to bind to iC3b, C3dg, or C3d. This additional binding makes the B cells 100- to 10,000-fold more sensitive to antigen. CR2 on mature B cells forms a complex with CD19 and CD81. This complex is called the B cell coreceptor complex for such sensitivity enhancement to the antigen.
Applications
Abatacept (Orencia) is a T cell co-stimulation modulator approved for the treatment of rheumatoid arthritis. The cytokines secreted by activated T cells are thought to both initiate and propagate the immunologically driven inflammation associated with rheumatoid arthritis. Orencia, a soluble fusion protein, works by altering the co-stimulatory signal required for full T-cell activation. Belatacept is another novel molecule which is being tested for use in renal transplantation.
A new co-stimulatory superagonistic drug, TGN1412, was the subject of a clinical trial at Northwick Park Hospital, London. The trial became surrounded in controversy as the six volunteers became seriously ill within minutes of being given the drug.
In essence, the co-stimulatory molecules function as "flashing red lights" that interact with the T cell, communicating that the material being presented by the dendritic cell material indicates danger. Dendritic cells displaying co-stimulatory molecules while presenting antigen are able to activate T cells. In contrast, T cells that recognize antigen presented by a dendritic cell not displaying co-stimulatory molecules are generally driven to apoptosis, or may become unresponsive to future encounters with the antigen.