Fig. 9.46 Effector molecules are released from T-cell granules in a highly polar fashion. The granules of cytotoxic T cells can be labeled with fluorescent dyes, allowing the granules to be seen under the microscope and their movements to be followed by time-lapse photography. here we show a series of pictures taken during the interaction of a cytotoxic T cell with a target cell, which is eventually killed. In the top panel, at time 0, the T cell (upper right) has just made contact with a target cell (diagonally below). at this time, the granules of the T cell, labeled with a red fluorescent dye, are distant from the point of contact. In the second panel, after 1 minute has elapsed, the granules have begun to move toward the target cell, a move that has essentially been completed in the third panel, after 4 minutes. after 40 minutes, in the last panel, the granule contents have been released into the space between the T cell and the target, which has begun to undergo apoptosis (note the fragmented nucleus). The T cell will now disengage from the target cell, whereupon it can go on to recognize and kill other targets. photographs courtesy of G. Griffiths.
9-33 Cytotoxic T cells also act by releasing cytokines.
Inducing apoptosis in target cells is the main way in which CD8 cytotoxic T cells eliminate infection. However, most CD8 cytotoxic T cells also release the cytokines IFN-γ, TNF-α, and LT-α, which contribute to host defense in other ways. IFN-γ inhibits viral replication directly, and induces the increased expression of MHC class I molecules and of other proteins that are involved in peptide loading of these newly synthesized MHC class I molecules in infected cells. This increases the chance that infected cells will be recognized as target cells for cytotoxic attack. IFN-γ also activates macrophages, recruiting them to sites of infection, where they serve both as effector cells and as antigen-presenting cells. TNF-α and LT-α can synergize with IFN-γ in macrophage activation via TNFR-II, and can kill some target cells through their interaction with TNFR-I, which can induce apoptosis (see Sections 9-28 and 9-29). Thus, effector CD8 cytotoxic T cells act in a variety of ways to limit the spread of cytosolic pathogens.
Summary.
Effector CD8 cytotoxic T cells are essential in host defense against pathogens that reside in the cytosol: most commonly these will be viruses. These cytotoxic T cells can kill any cell harboring such pathogens by recognizing foreign peptides that are transported to the cell surface bound to MHC class I molecules. CD8 cytotoxic T cells perform their killing function by releasing three types of preformed cytotoxic proteins: granzymes, which use multiple mechanisms to induce apoptosis in any type of target cell; perforin, which acts in the delivery of granzymes into the target cell; and granulysin, which has antimicrobial activity and is pro-apoptotic. These properties allow the cytotoxic T cell to attack and destroy virtually any cell infected with a cytosolic pathogen. The membrane-bound Fas ligand, expressed by CD8 and some CD4 T cells, may also induce apoptosis by binding to Fas, which is expressed on some target cells. However, this pathway is less important in most infections than that mediated by cytotoxic granules. CD8 cytotoxic T cells also produce IFN-γ, which inhibits viral replication and is an important inducer of MHC class I molecule expression and macrophage activation. Cytotoxic T cells kill infected targets with great precision, sparing adjacent normal cells. This precision is crucial in minimizing tissue damage while allowing the eradication of infected cells.
Summary to Chapter 9.