(1) Proliferation: increasing the frequency of the specific cells that can help in this particular instance.
(2) Differentiation: develops one of two ways to kill other cells: cytotoxicity and production of cytokines.
The Necessity of Cytotoxic Function
Cytotoxicity is needed for the elimination of many types of viral infection
Needed to control neoplastic growth (kill transformed cells before they become tumors)
Involved in the rejection of sold organ transplants
The only way to get rid of infected or otherwise damaged cells. Dead cells do not go onto make virus particles or tumors. Thus cytotoxicity prevents cells from being used for purposes other than their intended purposes.
The T cell interacts with virally infected cell very closely
it only wants to kill the cell that is infected
cell must have adherence molecules (LFA-1/ICAM-1)
the T cell programs the target cell to undergo apoptosis. The target cell "blebs" and eventually gets "holes" and dies. Once done the T cell moves on to find another cell that needs killing.
NEED LFA-1/ICAM and CD2/LFA3 contact
The cytotoxic T lymphocyte will bind to targets that have the antigen for the TCR.
Enzymes Caspases mediate Protease and DNA-ase activities.
Fragments eaten by Macrophages. The cell simply doesn’t exist anymore.
Cytotoxicity by Granular Exocytosis
Cytotoxic granules are secreted onto the surface of the target cell. ("targeted" only on the surface of the cell it wants to kill)
Perforin –
a pore forming molecule that creates a hole for Granzymes to go through.
Granulysin –
a pore forming molecule
Granzymes A and B –
enzymes that access the caspase pathway for apoptosis
We do not want the cellular contents released "willy-nilly"; the pores made allow granzymes in to trigger the well regulated apoptosis leading to an orderly destruction of the cell.
T-cells do not get killed by these enzymes because the membranes of cytotoxic cells have molecules that inactivate the pore forming substances and keep them from perforating their own membranes.
Cytotoxic cell have lots of granules- can hit many targets before running out of juice.
Cytotoxicity by Fas/Fas Ligand Apoptotic Pathway
redundant systems in the immune system to combat pathogens that can thwart the other pathways
Fas (CD 95) is expressed on most cells
Fas ligand is expressed on CTL, NK cells, and monocytes, also on other cells in the body (Seritoli cells, Corneal cells, Iris cells) {the testis and the eye are two places that act differently than the rest of the body- grafts will not be rejected}
Ligation of Fas/Fas ligand can result in induction of apoptosis of the Fas expressing cell
Depends on an intact intracellular pathway of enzymatic events leading to apoptosis.
Clinical applications of this pathway:
(1) Fas mutation causes Autoimmunity and Lymphoproliferation Syndrome (ALPS)
(2) Toxic Epidermal Necrolysis is inhibited clinically by the inhibition of the Fas/Fas ligand apoptotic pathway via IVIG (disease of skin sloughing caused by defective Fas/Fas ligand)
(3) This pathway is implicated in liver disease (HBC,HBV, EtOHism, Wilson’s tumor, etc)
Cells Involved in Cytotoxicity
(1) Cytotoxic T Lymphocytes
Circulate without cytotoxic potential- get activated then become cytotoxic
Mainly CD8 but some CD4
Differentiation influenced by: a) IL-2 and IL-12 2) By ligation of CD-40 on APC with CD-40 ligand on T-cell
(2) Natural Killer Cells
Surface expression of CD-16, CD-56, CD-11a/CD-18, CD-7, CD-8, and CD-57
Constituently cytotoxic, circulate "locked and loaded"
Differentiation enhances cytotoxic function, and is dependent on IL-2 and IL-12
(3) NK Recognition of Target Cells
Recognize Fc receptor (CD-16) antigenic recognition directed by immunoglobulins
Recognize MHC Class 1 molecules and turn off. If there is no MHC Class 1 expressed on the target the NK cell’s cytotoxic effects are not turned off and therefore they kill.
mechanisms – same as the CTL only the recognition is different