Interleukin (IL)-17 is a proinflammatory cytokine that has been implicated in mucosal neutrophil recruitment by regulating cytokines that mediate granulopoiesis as well as the local production of CXCR2 ligands that are chemoattractants for neutrophils (1). IL-17 has been found to be elevated in many inflammatory lung diseases, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (2). Moreover, Concanavalin A resimulation of draining lymph nodes cells from the lungs of patients with CF secrete substantially greater amounts of IL-17 compared with those from control patients without CF (3). However, the cellular sources of IL-17 in CF have not be clearly demonstrated in lung tissue. In this issue of the Journal (pp. 252), Tan and colleagues elegantly demonstrate the complexity of determining the source and significance of IL-17–producing cells in CF (4). While they demonstrate that CD4⁺ Th17 cells are prominently featured in the airway walls in established CF as well as newly diagnosed patients with CF and non-CF bronchiectasis, the authors also demonstrate that nature killer (NK) T cells and γδ Tcells are also sources of IL-17 in humans (Figure 1). These findings highlight a number of key points. First, IL-17 and Th17 cells are not only found in end-stage CF lung disease, but are clearly identifiable in young patients with incipient disease. Second, while CD4⁺ T cells are the most abundant group of IL-17⁺ T cells in the airways, NK T cells are also identified in end-stage lung disease and γδ T cells are noted in all disease groups studied. Combined with the BAL fluid data, these histopathologic findings yield a more complete picture of IL-17–driven inflammation in the CF airway.

Figure 1. Image reprinted from the U.S. Environmental protection Agency website (http://www.epa.gov/airtrends/ozone.html, accessed April 2, 2011).

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As the authors point out, these studies are limited in that they are cross-sectional in nature and the authors cannot definitively correlate T cell distribution, function, IL-17 levels, and disease course in CF. Thus, although IL-17–positive cells are found in CF, their contributions to lung disease remain to be determined. The authors speculate that Th-17 activity is the driving force behind inflammation in CF and that perhaps Th17 cells launch an inflammatory salvo that is answered by IL-17–producing neutrophils, establishing Th17 cells as the initiating factor. While this may occur, prospective and interventional studies would be needed to demonstrate this mechanistically.

To understand the Th17 pathway, alternative hypotheses about the establishment of Th17-mediated inflammation must also be entertained. While NK T cells are part of the innate immune response and have been previously shown to produce IL-17 (5), IL-17–producing NK T cells were only seen prominently in lung sections from end-stage lung disease and not in endobronchial samples from patients with incipient CF and non-CF bronchiectasis. While it is possible that there is sampling bias based on technique, these findings suggest that this T cell population may not be as important in early CF airway disease. Conducting further studies that can more definitively reconcile the role of NK T cells as innate inflammatory mediators and their absence in early CF airway disease is warranted.

The authors also describe IL-17–expressing γδ T cells that were seen in all patient populations on endobronchial biopsy and should bear closer scrutiny for this reason. γδ T cells are a unique T cell population because they function as part of the innate immune response, and are capable of responding to cytokine signals in the absence of antigen (6), demonstrating antigen specificity but requiring neither priming nor recruitment to the site of infection. As such, they are poised to produce IL-17 during the earliest stages of infection (5, 7). And, as infection progresses, persistent IL-17 production may promote polarization of Th0 cells toward a Th17 phenotype. While high levels of IL-17 may function as part of a negative feedback loop to inhibit further IL-17 production (7), prior studies also demonstrate that IL-17 promotes the production of IL-6, IL-21, and IL-1β, cytokines that polarize Th0 cells toward a Th17 phenotype (9–14). These findings suggest that while IL-17 production may not directly amplify further IL-17 production, if the inflammatory stimuli that prompt that initial IL-17 production persist, further IL-17 production will be promoted through the polarization of the adaptive immune response to a Th17 phenotype. Further, IL-17 inhibits the development of Th1 polarization (15).

Under normal circumstances, where resolution of infection is expected, the development of a memory response is protective and should result in more efficient clearance of pathogen with subsequent infections. In the case of CF, the inability to clear Pseudomonas aeruginosa due to abnormalities in the airway surface liquid and ciliary function leads to persisting activation of inflammatory pathways that promote chronic IL-17 production and the development of a Th17 phenotype (3, 16–18). The persisting neutrophilia cannot effectively clear pathogen (19, 20), and further neutrophil recruitment (21) and chronic infection (22–24) are promoted. For these reasons, a clear understanding of the IL-17/Th17 pathways is critical to determining whether anti–IL-17 therapy, or therapy targeted at its cellular sources, may be helpful in preventing inflammation-mediated damage. The challenges of developing safe and effective immunosuppressive therapy are significant. Adequate detail and resolution in our understanding of these pathways is necessary but may not be sufficient to do this.

This study provides the first systematic description of cellular sources of IL-17 in the CF airway. It provides a basis for more mechanistic studies to determine the sequence of events and relative importance of these cell populations in producing IL-17 and promoting airway damage during P. aeruginosa airway infection. It will be the challenge of investigators and clinicians to integrate these findings and develop and manage immunotherapies that can act as adjunctive treatments in CF.

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