T-Lymphocytes - Chronic Obstructive Pulmonary Disease - page 232

initiated when Fas binds to Fas-ligand, expressed on activated T-cells (190).
This pathway appears to be active in all killer cell lineages but most impor-
tant for CD4 þ T-cells, especially those of the Th-1 phenotype (191). In vivo
transplantation experiments suggest that the perforin = granzyme pathway
dominates the MHC Class I elimination pathway (CD8 þ CTLs) and that
Fas = FasL dominates the MHC Class II (CD4 þ ) elimination pathway
(192,193). It has been proposed that the Fas pathway may have primarily
an immunoregulatory role and to a lesser extent, an immune effector role
(194,195).
In addition to killing infected, injured, or stressed cells directly, CD8 þ
T-cells also produce a number of cytokines including TNF-a lymphotoxin
and IFN-g, a so-called Tc-1 phenotype (Tc for cytolytic T-cell) and can
behave as CD4 þ Th-1 (for T-helper) lymphocytes. There is evidence that
CD8 þ in the lungs of COPD patients expresses IFN-g (10,147), but interest-
ingly no perforin expression has been documented in the lungs of patients
with COPD. All these cytokines would enhance the inflammatory reaction
in the lung besides the direct killing by CD8 þ CTL.
There is experimental evidence of the unique role of CD8 þ T-cells in
causing lung damage and their capacity to recruit other inflammatory cells
to the lung. Enelow et al. (196) examined the specific impact of autoantigen
recognition by CTLs on pulmonary structure and function using a mouse
model, expressing a transgene for influenza virus hemagglutining (HA) in
the lung. Adoptive transfer of HA-specific CD8 þ CTLs lead to the develop-
ment of lethal injury in the transgenic mice and the injury was restricted to
the lung. The earliest finding in the lung was a loss of alveolar epithelial
cells, a result of direct cytolysis by CD8 þ CTLs, followed by the accumula-
tion of a mononuclear inflammatory infiltrate in the lung parenchyma, com-
prised mainly of alveolar macrophages, but also other inflammatory cells
(197,198). It has been shown that the process of apoptosis, including that
induced by CTLs, can be an important stimulus in the release of proinflam-
matory mediators and accounts for the important inflammatory infiltrate
found in these studies (187,199).
The effector functions of the CD4 þ T-cell are mainly mediated by
cytokines, Th-1 in our discussion. Essentially, once T-cells (CD4 þ and
CD8 þ ) are activated and home to the lung (in our case) source of the anti-
gens, they stimulate much greater leukocyte migration, the so-called
''immune inflammation'' (to indicate the role of the T-cells in the process).
Endothelial cells and alveolar macrophages are probably the two MHC
Class II endowed cells that would attract CD4 þ into the lung (10).
Once in the lung and activated, Th-1 CD4 þ (and Tc-1 CD8 þ ) T-cells
will express TNF-a and chemokines, and induce ligands for leukocyte adhe-
sion molecules promoting their attachment to the endothelium, while the
chemokines promote the transendothelial migration into the extravascular
tissue. Activated T-cells provide a very sustained source of these cytokines.