Although the contribution of CD8+ T cells to the pathogenesis of
noncommunicable lung diseases has become increasingly appreciated, our
knowledge about the mechanisms controlling self-reactive CD8+ T cells in the
respiratory tract remains largely elusive. The outcome of the encounter
between pulmonary self-antigen and naive CD8+ T cells, in the presence or
absence of inflammation, was traced after adoptive transfer of fluorescence-
labeled CD8+ T cells specific for the neo–self-antigen influenza A
hemagglutinin into transgenic mice expressing hemagglutinin specifically in
alveolar type II epithelial cells in order: to study the outcome of alveolar
antigen encounter in the steady state and under inflammatory conditions; to
define the phenotype and fate of CD8+ T cells primed in the respiratory tract;
and, finally, to correlate these findings with the onset of autoimmunity in
the lung. We found that CD8+ T cells remain ignorant in the steady state,
whereas transient proliferation of self-reactive CD8+ T cells is induced by
forced maturation or licensing of dendritic cells, increases in the antigenic
threshold, and targeted release of alveolar self-antigen by epithelial injury.
However, these cells fail to acquire effector functions, lack the expression
of the high-affinity IL-2 receptor CD25, and do not precipitate autoimmunity
in the lung. We conclude that inadvertent activation of CD8+ T cells in the
lung is prevented in the absence of “danger signals,” whereas tissue damage
after infection or noninfectious inflammation creates an environment that
allows the priming of previously ignorant T cells. Failure in effector cell
differentiation after abortive priming, however, precludes the establishment
of self-perpetuating autoimmunity in the lung
