T cells (produced in the thymus) circulate throughout the body until they recognise foreign particles (antigens) on the surface of antigen presenting cells (APCs). In addition to T cell receptor (TCR) binding to antigen-loaded MHC (Figure 1, arrow), both helper T cells and cytotoxic T cells require a number of secondary signals to become activated and respond to the threat. In the case of helper T cells, the first of these is provided by CD28. This molecule on the T cell binds to one of two molecules on the APC – B7.1 (CD80) or B7.2 (CD86) – and initiates T-cell proliferation. This process leads to the production of many millions of T cells that recognise the antigen. In order to control the response, stimulation of CD28 by B7 induces the production of CTLA-4 (CD152). This molecule competes with CD28 for B7 and so reduces activation signals to the T cell and winds down the immune response. Cytotoxic T cells are less reliant on CD28 for activation but do require signals from other co-stimulatory molecules such as CD70 and 4-1BB (CD137).
T cells must recognise foreign antigen strongly and specifically to mount an effective immune response and those that do are given survival signals by several molecules, including ICOS, 4-1BB and OX40. These molecules are found on the T-cell surface and are stimulated by their respective ligands which are typically found on APCs. Signalling through these co-stimulators leads to the up-regulation of anti-apoptotic proteins in the T cell, such as BCL-2 family members. Some T cells fail to respond appropriately to antigen and are killed in a process called activation-induced cell death (AICD). AICD also clears T cells at the end of an immune response unless they receive instruction to enter the memory cell pool.
Unlike CD28 and the TCR, ICOS, OX40 and 4-1BB are not constitutively expressed on T cells (Figure 2). Likewise, their respective ligands are only expressed on APCs following pathogen recognition. APCs are able to recognise conserved molecular motifs that are commonly found on pathogens and rarely found in the host. These pathogen-associated molecular patterns are recognised by receptors known as Toll-like receptors (TLRs).
Figure 2. Adapted from Gwyer et al., Biochem. Soc. Trans. (2006) 34, (1032–1036)
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