Activation or Suppression? T Cell Immunity in COPD Lungs

Leukocytes are resident in the lungs of healthy individuals and are necessary for defending against potentially harmful foreign antigens that are exposed to the lung on a constant basis. However, this immune defense comes at a cost as inappropriate regulation of pulmonary immune function has significant consequences and contributes to a number of lung disorders including COPD. Indeed, chronic inflammation is a hallmark of COPD and the extent of inflammation has been positively correlated with disease severity ([1]).

Lung immune protection is achieved by innate and adaptive arms of the immune system. Innate immunity is carried out on a rapid time scale by leukocytes such as macrophages and neutrophils that clear pathogens and noxious substances in an indiscriminate manner. In contrast, adaptive immunity is slower to develop but is specific for the offending foreign antigen or pathogen and requires coordinated interaction and response of multiple cell types that include T and B lymphocytes and dendritic cells. Of interest, an elevated presence of T lymphocytes has been repeatedly shown in individuals with COPD (reviewed in ref. 2) although precisely what role these adaptive immune cells play in disease pathogenesis has yet to be determined. In this issue of COPD Roos-Engstrand et al. ([3]) compare the presence and phenotype of airway T lymphocytes between individuals with COPD (both current and former smokers), individuals who have never smoked and those who smoke but have normal lung function. In focusing on these cohorts, the authors are able to comment on how smoking impacts the presence and phenotype of this lymphocyte population.

Several noteworthy findings are reported by Roos-Engstrand et al. and include the observation that COPD individuals harbor an elevated presence of activated CD8 T cells independent of whether they were current or ex-smokers. Furthermore, and confirming previously reports, an increased number of CD4+CD25+ regulatory T cells were also found in COPD patients. Considered together, these data present an interesting dichotomy. On the one hand, regulatory T cells are generally considered to repress immune responses. On the other hand, the presence of activated CD8 T cells suggests that these T cells are being stimulated and may be directly contributing to the pathogenesis of COPD. Based on the increase of these cell types in COPD patients (both smokers and ex-smokers), the authors speculate that both cytotoxic CD8 T cell responses and immunosuppressive mechanisms may be important in COPD pathogenesis.

Exactly what CD8 T cells are doing in the lungs of COPD patients and why they appear to be spared from the immune suppressive effects of regulatory T cells is unclear but deserves attention. The primary functions of cytotoxic CD8 T cells are to recognize and destroy cells expressing a stimulating ligand (e.g. a viral antigen), and to produce cytokines such as interferon-gamma that can direct effects on surrounding cells and other leukocytes. While regulatory T cells use multiple mechanisms to suppress immune responses ([4], [5]), the function of these regulatory T cells can also be impaired by certain inflammatory conditions ([6]). Clearly, future studies will be required to better elucidate the role of these cytotoxic CD8 T cells and regulatory T cells in the lungs of COPD patients.

Given the presence of both T cell populations in the lungs of COPD patients, one major question arising is what kinds of antigens these T cell populations might be recognizing. Roos-Engstrand et al. propose that the CD8 T cells might be responding to a stress-induced ligand, an infectious agent, or perhaps self-antigens. While these explanations are based on the idea that cytotoxic T cells are being actively stimulated by an antigen in the COPD lung, it is worth noting that the lung environment itself can promote acquisition of activation markers on cytotoxic T cells even in the absence of ongoing antigenic stimulation ([7]).

The data presented by Roos-Engstrand et al. are consistent with others in showing both more regulatory T cells ([8], [9]) and CD8 T cells in COPD lungs (reviewed in ref. 2). While all groups agree that regulatory T cells are increased in smokers, previous work by Barcelo et al. presented data that COPD patients had fewer regulatory T cells than healthy smokers ([8]) and hypothesized that an insufficient number of regulatory T cells to CD8 T cells may contribute to COPD. While Roos-Engstrand et al. present similar findings, they further demonstrate that smoking clearly contributes to the abundance of regulatory T cells in the lung (COPD smokers had higher regulatory T cell populations that COPD ex-smokers). Notably COPD ex-smokers also had higher regulatory T cell populations than non-smokers. These data suggest that increased regulatory T cell populations result from contributions by both smoking and COPD, and further stress the need to examine lymphocyte populations in COPD patients who are smokers and ex-smokers.

Finally, although regulatory T cells are often defined by expression of the CD4 and CD25 surface receptors, CD25 (the IL-2 receptor alpha chain) can also be expressed upon lymphocyte activation. Thus, in the future it will be important to definitively demonstrate that these cells are bona fide regulatory T cells by documenting the expression of the FoxP3 transcriptional regulator ([10]), which is critical for the development and function of regulatory T cells.