Which processes drive the accumulation of cytotoxic CD8+ T cells in the lungs of COPD patients?

Since increased numbers of CD8+ T cells have been found in various tissue
compartments in COPD lungs, it has been hypothesized that these cells are
implicated in the pathogenesis of COPD. However, it is far from established
whether, and if yes how, these cells contribute to the development of COPD in
smokers. Increased insight into these mechanisms may come from knowledge of the
processes that drive the accumulation of CD8+ T cells in lung tissue.
From studies on the cell surface phenotype of CD8+ T cells in various phases of
viral infections much has been learned about the biology of these cells that,
however, generally were isolated from the circulation. We recently started to
study CD8+ T cells isolated from human lung tissue. It became clear that lung
residing CD8+ T cells have quite a different phenotype than their peripheral
blood counterparts. Specifically, the main findings from our initial study were
(1) the local accumulation of resting but differentiated CD8+ T-lymphocytes
specific for cleared respiratory viruses, (2) the presence of high numbers
activated CD4+ and CD8+ T cells of yet undetermined specificity in the lung and
(3) the low activation threshold of lung residing T cells. In addition, our
findings from a recently finished NAF project support a role for Granzyme B and
Granzyme B+ CD8+ T-lymphocytes in the development towards COPD in cigarette
smokers. Altogether, however, these data leave a number of relevant questions
open, especially in relation to the mechanisms regulating the homeostasis of
lung residing CD8+ T cells.

In the present project we aim to characterize the lung CD8+ T cell immune
system and analyse if differences exist between *healthy* smokers and COPD
patients. If so, these data will help to clarify the (immuno)pathogenesis of
COPD. Specifically, we will analyze (1) if the long T cells are maintained
through homeostatic control mechanisms distinct from the circulating pool
(replicative history measurements), (2) if within the lung selection of
particular T cell clones occurs (spectratyping) and (3) the transcriptosome of
lung T cells (DNA microarrays). Where possible we will use HLA/*2-
microglobuline/viral peptide tetramers to perform the analyses on established
virus specific T cells.
A major limitation in current research is the lack of longitudinal studies in
smokers at risk to evaluate changes in the local T cell compartment. As a first
step we aim to compare BAL from and tissue isolated T cells. In case BAL
derived T cells would appear to be representative of tissue residing T cells,
BAL T lymphocytes may be used to monitor changes in the local T cell
compartment in longitudinal studies.
Understanding the mechanisms that drive the homing and functional
differentiation of CD8+ T-cells in the lungs in COPD helps to understand their
involvement in its pathogenesis. Insight into the molecular mechanisms may give
guidance to develop specific interventions to rebalance this process. This may
ultimately lead to specific interventions that can stop or slow the progression
in COPD

observational study

There is no real risk and only a minimaal burden for the lung transplantation
patients: only that related to a venapuncture or of taking some extra blood
during a regular sampling of blood.

For the lobectomy patients there is a minimal burden related to a venapuncture
or of taking some extra blood during a regular sampling of blood.
The sputuminduction may give a light, generally shortlasting sensation of
dysnea in patients with COPD.
The risks for the lobectomy patients are minimal related to the
sputuminduction, provided that the right precautions are taken and the patients
are closely observed. The same holds for the BAL procedure in patients
intubated and during the regular monitoring during general anesthesia.

For (ex-)smokers with established COPD there is a potential group benefit in
that the findings of the study may lead to new insights into the pathogenesis
of COPD and possible new therapies.