T-Cell Mediated Cytotoxicity

1.            Introduction

a.         All viruses, and some bacteria, multiply in the cytoplasm of infected cells.

b.         Once inside cells, these pathogens are not accessible to antibodies and can be eliminated only by the destruction or modification of the infected cells on which they depend.

c.         This role in host defense is fulfilled by cytotoxic CD8 T cells.

d.         As well as controlling infection by viruses and cytoplasmic bacteria, CD8 T cells are important in controlling some protozoan infections.

e.         The elimination of infected cells without destruction of healthy tissues requires the cytotoxic mechanisms of CD8 T cells to be both powerful and accurately targeted.

2.            Actions of CD8 Cytotoxic T cells

a.         Armed CD8 cytotoxic effector T cells are essential in host defense against pathogens that live in the cytosol.

b.         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 1 proteins.

c.         This prevents the spread of the cytosolic pathogens to other normal functioning cells.

d.         CD8 cytotoxic T cells carry their killing functions by releasing:

i.            granzymes: induce apoptosis in target cell.

ii.            perforin: punches holes in the target-cell membrane through which the granzymes enter.

e.         A membrane-bound molecule, the Fas ligand, expressed by CD8 and some CD4 T cells, is also capable of inducing apoptosis by binding to Fas on target cells.

f.          CD8 cytotoxic T cells also release the cytokines IFN-g, TNF-a and TNF-b which contribute to host defense in several other ways.

g.         Role of IFN-g in immune response:

i.          directly inhibits viral replication.

ii.          induces increased expression of MHC class 1 and peptide transporter molecules in infected cells.

iii.            activates macrophages, recruiting them to sites of infection, both as effector cells and as antigen-presenting cells.

h.         TNF-a or TNF-b can synergize with IFN-g in macrophage activation, and in killing some target cells through a cytokine-mediated pathway.

3.            Macrophage activation by armed CD4 TH1 cells

a.            Intracellular microorganisms in Macrophages:

i.          some microorganisms, such as mycobacteria, the causative agents of tuberculosis and leprosy, are intracellular pathogens that grow in phagolysosomes of macrophages.

ii.          there they are shielded from the effects of both antibodies and cytotoxic T cells.

iii.         these microbes maintain themselves in the usually hostile environment of the phagocyte by inhibiting lysosomal fusion to the phagolysosomes in which they grow, or by preventing acidification of these vesicles.

iv.         such microorganisms are eliminated when the macrophage is activated by a TH1 cell.

b.         Mode of action of TH1 cells:

i.            synthesis of membrane-associated proteins and soluble cytokines whose local and distant actions coordinate the immune response to these intracellular pathogens.

ii.          activate macrophages to kill recently ingested pathogens.

c.            Activation of TH1 cells:

i.          the activation of TH1 cells requires that recognize a complex on the surface of antigen presenting cells, e.g. macrophages, consisting of both the antigen and a class II MHC protein.

ii.          within the cytoplasm of the macrophage, the foreign protein is cleaved into small peptides that associate with the class II MHC proteins.

iii.         the complex is transported to the surface of the macrophage, where the antigen, in association with a class II MHC protein, is presented to the receptor on the TH1 cell.

d.            Activation of Macrophages:

i.          when a TH1 cell specific for a bacterial peptide contacts an infected macrophage, the T cell is induced to secrete IFN-g and to express CD40 ligand.

ii.            together, these newly synthesized TH1 proteins activate the macrophage.

e.         Role of TH1 Cytokines in Immune response:

f.            Formation of Granulomas:

i.          when mycobacteria resist the effects of macrophage activation, a characteristic localized inflammatory response called a granuloma develops.

ii.          this consists of a central core of infected macrophages.

iii.         the core may include multinucleated giant cells, which are fused macrophages, surrounded by large macrophages called epitheloid cells.

iv.            mycobacteria can persist in the cells of the granuloma.

v.         in tuberculosis, the center of the large granulomas can become isolated and the cells there die, from a combination of lack of oxygen and the cytotoxic effects of activated macrophages.

vi.         the process is called caseous necrosis.

4.            Antibody-dependent cellular cytotoxicity

a.         In addition to direct killing by cytotoxic T cells, virus-infected cells can be destroyed by a combination of IgG and phagocytic cells.

b.            Antibody bound to the surface of the infected cell is recognized by IgG receptors on the surface of phagocytic cells, e.g. macrophages or NK cells, and the infected cell is killed.

c.         The ADCC process can also kill helminths (worms).

d.         In this case, IgE is the antibody involved and eosinophils are the effector cells:

i.          IgE binds to surface proteins on the worm.

ii.          the major basic protein located in the granules of the eosinophils is released and damages the surface of the worm.

e.            Immunosurveillance:

i.          many tumor cells develop new antigens on their surface.

ii.          these antigens are bound to class I proteins are recognized by cytotoxic T cells, which are stimulated to proliferate by IL-2.

iii.         the resultant clone of cytotoxic T cells can kill the tumor cells.