Elimination of antigen leads to contraction of the T-cell response, and this decline is responsible for maintaining homeostasis in the immune system. Several mechanisms may account for the decline.
• Cell death. As the antigen is eliminated and the innate immune response associated with antigen exposure abates, the signals that normally keep activated lymphocytes alive and proliferating are no longer present. As mentioned earlier, costimulation and growth factors such as IL-2 stimulate expression of the anti-apoptotic proteins BCL-2 and BCL XL in the activated lymphocytes, and these proteins keep cells viable. As the level of costimulation and the amount of available IL-2 decrease, the levels of anti-apoptotic proteins in the cells drop. At the same time, growth factor deprivation activates sensors of cellular stress (such as the BH3-only protein BIM), which trigger the mitochondrial pathway of apoptosis and are no longer opposed by the anti-apoptotic proteins (see Fig. 1). The net result of these changes is that most of the cells that were produced by activation die and the generation of newly activated cells declines, so the pool of antigen-activated lymphocytes contracts.
• Inhibition of T-cell activation. A number of mechanisms inhibit T-cell responses after they have been initiated. These mechanisms likely contribute to physiological downregulation of immune responses to pathogens, and they also are important in maintenance of self-tolerance.
• Reduced activating signals. Several intracellular enzymes function to limit the duration or magnitude of T-cell activation responses. These include phosphatases such as SHP1, SHP2, and SHIP, which dephosphorylate signaling substrates, and E3 ubiquitin ligases such as CBL-b, which degrade activated signaling intermediates. These enzymes may be activated after TCR and costimulatory pathways are engaged.
• Engagement of cell surface inhibitory molecules. As mentioned earlier, PD-1 and CTLA-4 both function to limit continued activation of T cells. It is clear that these coinhibitors regulate T-cell responses to repeated antigenic exposure (e.g., to self and tumor antigens and in the con text of chronic infections), but they likely play more limited roles in regulating responses to most acute microbial infections and vaccines.
• Regulatory T cells. Many immune responses in which effector T cells are activated are accompanied by the expansion of regulatory T cells. Regulatory T cells function in several ways to limit continuing T-cell activation, including the engagement of CTLA-4 on their surface with B7 on APCs, as discussed further in Chapter 15. Regulatory T cells limit immunopathology during infection and also suppress autoimmunity and allergy.
Fig1. Pathways of apoptosis. Apoptosis is induced by the mitochondrial and death receptor pathways, described in the text. The executioner caspases activate endonucleases and other enzymes, whose actions culminate in fragmentation of the dead cell, and the apoptotic bodies are cleared by phagocytes. FAS-L, FAS ligand; TNF, tumor necrosis factor.
