Negative selection in the thymus is a major mechanism for ensuring that peripheral T cells do not react with host cells expressing MHC proteins with peptides derived from self proteins in their peptide-binding grooves. This mechanism, however, requires that the APCs in the thymus display an array of peptides on their MHC molecules that will reflect the self proteins in peripheral tissues, as well as in the thymus. The thymus, however, would not be expected to produce many of the proteins that are specifically expressed in other organs. As an example, it would not be expected to produce insulin, and yet it is crucial to delete thymocytes with TCRs that could recognize insulin-derived peptides bound to MHC
DEATH BY DEFAULT NEGATIVE SELECTION (signaled death) DEATH BY DEFAULT apoptotic cell TH POSITIVE SELECTION (signaled survival) SURVIVAL, MATURATION, and EMIGRATION TH TC TC Treg Treg proteins on the surface of insulin-secreting β cells in the pancreas. Any failure to do so would result in the T-cell-dependent destruction of the β cells and, as a consequence, cause type 1 (or juvenile) diabetes.
The mechanism that enables the deletion of all such cells in the thymus depends on a subpopulation of epithelial cells in the thymus that express a transcriptional regulator called AIRE (autoimmune regulator). By a poorly understood mechanism, the AIRE protein promotes the production of small amounts of mRNA from many genes that encode such “organ-specific” proteins, including the insulin gene. When the peptides derived from the proteins encoded by these genes are bound by MHC proteins and displayed on the surface of the epithelial cells in the thymus medulla, this is sufficient to provoke the deletion of the potentially self-reactive thymocytes. Mutations that inactivate the AIRE gene cause a severe multiorgan autoimmune disease in both mice and humans, indicating the importance of AIRE in self-tolerance.
cytotoxic T cells Induce Infected Target cells to Kill Themselves
Cytotoxic T cells (TC cells), like the NK cells discussed earlier, protect us against intracellular pathogens, including viruses, bacteria, and parasites, that multiply in the cytoplasm of a host cell. TC cells kill infected host cells before the pathogen can escape to infect neighboring host cells. Before it can kill, however, a naïve TC cell has to become an effector cell by activation on an APC, usually an activated dendritic cell that has pathogen-derived peptides bound to class I MHC proteins—a process that depends on helper T cells. The effector TC cell can then recognize any target cell harboring the same pathogen and expressing some of the same peptide–MHC complexes on its surface: its TCRs cluster, along with CD8 co-receptors, adhesion molecules, and intracellular signaling proteins (discussed later), at the interface between the two cells, forming an immunological synapse. In this process, the effector TC cell reorganizes its cytoskeleton to focus its killing apparatus on the target cell, secreting its toxic proteins into a confined space (Figure 24–42); in this way, it avoids killing neighboring cells. A similar synapse forms when an effector helper T cell interacts with its target cell, except that the co-receptor is CD4 (Movie 24.11).