Costimulatory Proteins on Antigen-Presenting Cells Help Activate T Cells
To activate a cytotoxic or helper T cell to proliferate and differentiate into an effector cell, an antigen-presenting cell provides two kinds of signals. Signal 1 is provided by a foreign peptide bound to an MHC protein on the surface of the presenting cell. This peptide-MHC complex signals through the T cell receptor and its associated proteins. Signal 2 is provided by costimulatory proteins, especially the B7 proteins (CD80 and CD86), which are recognized by the co-receptor protein CD28 on the surface of the T cell. The expression of B7 proteins on an antigen-presenting cell is induced by pathogens during the innate response to an infection. Effector T cells act back to promote the expression of B7 proteins on antigen-presenting cells, creating a positive feedback loop that amplifies the T cell response.
Signal 2 is thought to amplify the intracellular signaling process triggered by signal 1. If a T cell receives signal 1 without signal 2, it may undergo apoptosis or become altered so that it can no longer be activated, even if it later receives both signals (Figure 24-62). This is one mechanism by which a T cell can become tolerant to self antigens.
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The T cell receptor does not act on its own to transmit signal 1 into the cell. It is associated with a complex of invariant transmembrane proteins called CD3, which transduces the binding of the peptide-MHC complex into intracellular signals (Figure 24-63). In addition, the CD4 and CD8 co-receptors play important parts in the signaling process, as illustrated in Figure 24-64.
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The combined actions of signal 1 and signal 2 stimulate the T cell to proliferate and begin to differentiate into an effector cell by a curiously indirect mechanism. In culture, they cause the T cells to stimulate their own proliferation and differentiation by inducing the cells to secrete a cytokine called interleukin-2 (IL-2) and simultaneously to synthesize high affinity cell-surface receptors that bind it. The binding of IL-2 to the IL-2 receptors activates intracellular signaling pathways that turn on genes that help the T cells to proliferate and differentiate into effector cells (Figure 24-65). As discussed in Chapter 15, there are advantages to such an autocrine mechanism. It helps ensure that T cells differentiate into effector cells only when substantial numbers of them respond to antigen simultaneously in the same location, such as in a lymph node during an infection. Only then do IL-2 levels rise high enough to be effective.
Once bound to the surface of an antigen-presenting cell, a T cell increases the strength of the binding by activating an integrin adhesion protein called lymphocyte-function-associated protein 1 (LFA-1). Activated LFA-1 now binds more strongly to its Ig-like ligand, intracellular adhesion molecule 1 (ICAM-1), on the surface of the presenting cell. This increased adhesion enables the T cell to remain bound to the antigen-presenting cell long enough for the T cell to become activated.
The activation of a T cell is controlled by negative feedback. During the activation process, the cell starts to express another cell-surface protein called CTLA-4, which acts to inhibit intracellular signaling. It resembles CD28, but it binds to B7 proteins on the surface of the antigen-presenting cell with much higher affinity than does CD28, and, when it does, it holds the activation process in check. Mice with a disrupted CTLA-4 gene die from a massive accumulation of activated T cells.
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Most of the T (and B) effector cells produced during an immune response must be eliminated after they have done their job. As antigen levels fall and the response subsides, effector cells are deprived of the antigen and cytokine stimulation that they need to survive, and the majority die by apoptosis. Only memory cells and some long-lived effector cells survive.
Table 24-3 summarizes some of the co-receptors and other accessory proteins found on the surface of T cells.
Before considering how effector helper T cells help activate macrophages and B cells, we need to discuss the two functionally distinct subclasses of effector helper T cells, TH1 and TH2 cells, and how they are generated.
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