Structural and functional consequences of alveolar cell recognition by CD8(+) T lymphocytes in experimental lung disease.

Abstract

CD8ϩ T cells infiltrate the lung in many clinical conditions, particularly in interstitial lung disease. The role(s) that CD8 ϩ T cells might be playing in the pathogenesis of inflammatory lung disease is unclear at present, as is the direct contribution of CD8 ϩ T cell effector activities to lung injury. This report describes a transgenic model used to evaluate the impact, on respiratory structure and function, of CD8 ϩ T lymphocyte recognition of a target antigen expressed endogenously in alveolar epithelial cells. We found that adoptive transfer of cloned CD8 ϩ cytotoxic T lymphocytes (CTLs) specific for an alveolar neo-antigen (influenza hemagglutinin) leads to progressive lethal injury in transgenic mice, which dramatically affects lung structure and function. Transgenic recipients of CD8 ϩ CTLs exhibited tachypnea and progressive weight loss, becoming moribund over a period of several days. Concomitantly, the animals developed a progressive interstitial pneumonitis characterized initially by lymphocytic infiltration of alveolar walls and spaces, followed by an exuberant mononuclear cell infiltration that correlated with restrictive pulmonary mechanics and a progressive diffusion impairment. These results indicate that antigen-specific CD8 ϩ T cell recognition of an alveolar epithelial "autoantigen" is, in and of itself, sufficient to trigger an inflammatory cascade that results in the histological and physiological manifestations of interstitial pneumonia. ( J. Clin. Invest. 1998. 102:1653-1661.)

CD4+CD25+Foxp3+ Regulatory T Cells Are Dispensable for Controlling CD8+ T Cell-Mediated Lung Inflammation

“…Moreover, an effector cytokine profile has been detected in CD8 + T cells isolated from patients with pulmonary disorders; the presence of these cytokines suggests that T cytotoxic type 1 (Tc1) cells make an important contribution to the pathologic findings associated with lung diseases (5,6). This finding was further supported by experimental data obtained from the adoptive transfer of Tc1 cells specific for a neo self-antigen expressed in the lungs of recipient mice; the transfer led to severe pulmonary inflammation and lethality within a few days (7).…”

Role of T-lymphocytes and pro-inflammatory mediators in the pathogenesis of chronic obstructive pulmonary disease

“…The potential for activated T-cells to cause lung injury in mice was evidenced after adoptive transfer of CD8 + T-cells with specifi cities for neoantigens that were expressed on alveolar epithelial cells (Enelow et al 1998). CD8 + T-lymphocytes were also recently shown to be critical for the induction of infl ammation and tissue destruction in a murine model of smoke-induced emphysema (Maeno et al 2007).…”

Inflammatory impact of IFN-γ in CD8+T cell-mediated lung injury is mediated by both Stat1-dependent and -independent pathways

“…However, it is difficult to separate the direct effects of the viral infection on lung pathology from the effects of the CD8 ϩ T cell effector functions, such as cytotoxicity and production of the proinflammatory cytokines IFN-␥ and TNF-␣. Using a transgenic mouse model of influenza infection in which influenza hemagglutinin (HA) is expressed by lung epithelial cells (6), we have identified critical mechanisms by which CD8 ϩ T cells mediate influenza immunopathology in the absence of replicating virus. We previously demonstrated that, following alveolar antigen recognition, TNF-␣ production by HA-specific CD8 ϩ T cells induced lung epithelial cell chemokine expression, which resulted in extensive airway inflammation and lethal lung injury (4,32).…”