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During the activation of T cells, co-stimulation is often crucial to the development of an effective immune response. T cells require two signals to become fully activated. A first signal, which is antigen-specific, is provided through the T cell receptor 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.
Applications
Orencia (abatacept) 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 recently 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-stiumlatory 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.
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