T-Lymphocytes - Chronic Obstructive Pulmonary Disease - page 231

perpetrated as long as the offending agent, cigarettes, continues to originate
an innate immune inflammation and antigenic products and sometimes, for
reasons that are not clear, after smoking cessation.
C. Effector Functions of CD8 þ and CD4 þ T-Cells
The designed role for CD8 þ T-cells is cytotoxicity. Na¨ve CD8 þ CTL T-cell
precursors have no cytotoxic activity and must undergo an activation pro-
cess (described above) requiring 1-3 days for maximal activity. This process
requires a TCR stimulated induction, with the co-operation of CD4 þ T-
cells, of cytokine receptors (e.g., IL-2 and IL-6). These cytokines then induce
the expression of a large array of granule components (186), including (a)
membrane-perturbing proteins—perforin and granulysin, (b) granule serine
proteases—granzymes A, B and also C, and others, (c) perforing inhibitors—
calveticulin and cathepsin b, and (d) stored T-cell effector molecules—Fas
ligand and possibly b-chemokines (187). These granules then reside in the
cytoplasm of the cell, where they await further instructions, i.e., their next
encounter with MHC Class I antigen bearing target cells (in the tissue where
antigens are originating).
After a cytolitic attack, target cells may die by necrosis, under the
effects of perforin and probably granulysin (188), and = or apoptosis. Apop-
tosis can be mediated by granzymes A, B in a caspase dependent, and also
independent manner targeting mitochondria and DNA degradation directly
(187).
As most, if not all, nucleated cells can express MHC Class I molecules,
any cell that, for some reason, presents antigens (virus infected, tumor, and
damaged cell) can be the target for a CD8 þ CTL, as long as the CD8 þ
T-cell has been primed by DCs for the antigen being presented. When gran-
ules are present, the killer cell orients its granules to the region of receptor
activation (TCR-MHC-1 binding site) and releases the granule components
into the region of contact between the killer and the target. This region of
contact is initiated by the receptor TCR, and then organized into an ''immu-
nological synapse'' formed by adhesion molecules (e.g., LFA-1 and ICAM-1
TCD-2) (187,188). The CD8 þ CTLs can kill multiple cells by reorienting
their granules to another region of contact, in contrast to natural killer cells
(NKCs), the innate immunity lymphocyte killers, which must rearm them-
selves in response to IL-2 before they are effective against new targets
(189). As reviewed before both necrotic debris and apoptotic cells are
powerful sources of antigenic material that could reach the DC (or macro-
phages) by HSPs or phagosomes and perpetrate the T-cell response.
The T-cells (CD8 þ and CD4 þ ) can also kill their targets by the Fas-
mediated pathways. Fas-(CD95) is a member of the TNF receptor family
that is expressed on the surface of T-cells and many other cells, and initiates
a signaling cascade leading to apoptotic cell death. The death pathway is