Cytotoxic T Cells Carry the CD8 Co-receptor and Are Specialized for Killing
As we have seen, cytotoxic T cells (CTLs) generally express on their surfaces the TCR co-receptor glycoprotein called CD8. These CD8+ T cells kill target cells that display their cognate class I MHC–peptide combinations and do so with exquisite sensitivity: a single MHC-peptide complex suffices to allow a properly activated CTL to kill the target cell that bears it.
The mechanism of killing by CTLs involves two classes of proteins that act synergistically: perforins and granzymes (Figure 23-34). Perforins, which exhibit homology to the terminal components of the complement cascade composing the membrane attack complex, form pores up to 20 nm across in membranes to which they attach. The destruction of an intact permeability barrier, which leads to loss of electrolytes and other small solutes, contributes to cell death. Granzymes are delivered to and are presumed to enter the target cell, probably via the pores generated by perforin. Granzymes are serine proteases that activate caspases and so propel the target cell on a path of programmed cell death (apoptosis; see Chapter 21). Perforins and granzymes are packaged into cytotoxic granules, which are stored inside the cytotoxic T cell. Upon binding of the T-cell receptor to its cognate class I MHC–antigen complex, signal transduction from the TCR leads to release of the cytotoxic granules and their contents into the extracellular space that is formed between the cytotoxic T cell and the target cell, called the immunological synapse. How the T cell avoids being killed upon release of granzymes and perforins into the synapse is unknown. Natural killer cells also exert cytotoxic activity and likewise rely on perforins and granzymes to kill their targets (see Figure 23-6).
FIGURE 23-34 Perforin- and granzyme-mediated cell killing by cytotoxic T cells. Upon recognition of a target cell (step 1), a cytotoxic T cell forms tight antigen-specific contact with the target cell. Tight contact results in the formation of a synaptic cleft, into which the contents of cytotoxic granules, including perforins and granzymes, are released (step 2). Perforins form pores in the membranes onto which they adsorb, and granzymes are serine proteases that enter through the perforin pores (step 3). Perforins are believed to act not only at the surface of the target cell, but also at the surface of its endosomal compartments after the perforin molecules have been internalized from the cell surface (step 4). Once in the cytoplasm, the granzymes activate caspases, which initiate programmed cell death (step 5).