Page 559 - Veterinary Immunology, 10th Edition

Perforin Pathway
VetBooks.ir The killing process can be divided into three phases: adhesion,

lethal hit, and cell death (see Fig. 18.8).

Adhesion Phase

When TCRs on cytotoxic T cells bind to antigen-MHC complexes on
the target cell, an immunological synapse rapidly forms around the
area of contact. The TCRs and other signaling molecules cluster at

one of the centers of the complex. The CD8 molecules bind target
cell MHC class I and strengthen T cell–target binding. If the TCR
has a very high affinity for the target antigen, co-stimulation
through CD8 may not be necessary.
In addition to receiving signals from antigen-MHC-CD8

complexes, cytotoxic T cells need co-stimulation. As with CD4
helper T cells, CD8 cytotoxic cells require signals from CD28 bound
to CD86 on the target cell. Additional adhesion between cytotoxic T

cells and their targets is mediated by T cell CD2 binding to target
cell CD58 (in non-rodents) or CD48 (in rodents) and T cell
CD11a/CD18 (LFA-1) binding to target cell CD54 (ICAM-1).

Lethal Hit

Within a few minutes of binding to a target, the T cells orientate
their microtubule organizing center, their Golgi complex, and their
granules toward the target cell. The cytoplasmic granules migrate
to the center of the synapse. Here they fuse with the T cell
membrane in such a way that the toxic granule contents are

inserted into the target. Cytotoxic T cell granules contain several
lethal molecules, of which the most important are perforins,
granzymes, and granulysin.

Perforins are pore-forming glycoproteins produced by cytotoxic
T cells and natural killer (NK) cells. Perforins insert themselves into
the target cell membrane and oligomerize to form tubular
transmembrane channels (Fig. 18.9). Between 19 and 24 perforin
monomers aggregate to form a circular membrane attack complex

that forms large (130-200 A) pores in target cell membranes. These
perforins are related to and act in a similar manner to C9, the
molecule that forms the terminal complement complex (Chapter 4).

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