Figure 24–41 Positive and negative selection in the thymus. Developing thymocytes with Tcrs that would potentially enable them to respond to peptides in association with self Mhc proteins after they leave the thymus are positively selected: the binding of their Tcrs to self peptides bound to self Mhc proteins in the thymus signals such cells to survive, mature, and migrate to peripheral lymphoid organs. All of the other thymocytes undergo apoptosis—either because they do not express Tcrs that recognize self Mhc proteins with self peptides bound or because they recognize such complexes too well and undergo negative selection.
The regulatory T cells (Treg cells) that are positively selected in the thymus are called natural Treg cells to distinguish them from induced Treg cells, which develop in peripheral lymphoid organs from naive helper T cells (Th cells), as we discuss shortly.
Figure 24–42 effector cytotoxic T cells killing target cells in culture. (A) electron micrograph showing an effector cytotoxic T cell (Tc cell) binding to a target cell. The Tc cells were obtained from mice immunized with the target cells, which are foreign tumor cells. (B) electron micrograph showing a Tc cell and a tumor cell that the Tc cell has killed. In an animal, as opposed to a culture dish, the killed target cell would be phagocytosed by neighboring cells (especially macrophages) long before it disintegrated in the way that it has here. (c) Immunofluorescence micrograph of a Tc cell and tumor cell after immunofluorescence staining with anti-tubulin antibodies. Note that the centrosome in the Tc cell is located at the point of cell–cell contact with the target cell—an immunological synapse. The secretory granules (not visible) in the Tc cell are initially transported along microtubules to the centrosome, which then moves to the synapse, delivering the granules to where they can release their contents. (A and B, from D. Zagury et al., Eur. J. Immunol. 5:818–822, 1975. With permission from John Wiley & Sons, Inc; c, from B. Geiger, D. rosen and G. Berke, J. Cell Biol. 95:137–143, 1982. With permission from the authors.)
An effector TC cell (or an NK cell) can employ one of two strategies to kill the target, both of which operate by inducing the target cell to activate caspases and kill itself by undergoing apoptosis. One mechanism uses a protein called Fas ligand on the killer-cell surface, which binds to a transmembrane receptor protein called Fas on the target cell; this mechanism is discussed in Chapter 18 (see Figure 18–5). The other mechanism is the main one used by both NK cells and TC cells to kill an infected target cell. The killer cell stores various toxic proteins within secretory vesicles in its cytoplasm that it releases into the synaptic space by exocytosis. The toxic proteins include perforin and proteases called granzymes. The perforin is homologous to complement component C9 and polymerizes in Figure 24–43 The main way that an the target-cell plasma membrane (see Figure 24–8), forming a transmembrane effector TC cell (or NK cell) kills an pore that disrupts the membrane and allows the granzymes to enter the target infected target cell. This simplified drawing shows how the killer cell releases cell. Once in the cytosol, the granzymes help activate caspases, thereby inducing perforin and granzymes onto the surface apoptosis (Figure 24–43).