Il-17a Promotes Pulmonary Dc And Macrophage Accumulation During The Transition From Th2 To Th1/th17 Responses Following Repetitive Challenge With Aspergillus Fumigatus

B. J. Murdock , R. A. McDonald , G. B. Toews , G. B. Huffnagle , J. J. Osterholzer

Author address: 

Univ of Michigan, Ann Arbor, MI, University of Michigan, Ann Arbor, MI, University of Michigan Medical School, Ann Arbor, MI, Ann Arbor VA Health System & University of Michigan, Ann Arbor, MI

Abstract: 

Rationale: Aspergillus fumigatus (Af), a ubiquitous airborne fungus, triggers allergic bronchopulmonary aspergillosis in a subset of otherwise healthy individuals. The mechanism(s) underlying this aberrant response to Af is poorly understood. We recently showed that repeated intranasal challenge of immunocompetent mice with viable Af conidia results in potent Th2-mediated allergic lung disease followed by a mixed Th1/Th17 immune response. In this study, we sought to further characterize the profile of lung antigen presenting cells (APC) and T cells throughout this dynamic immune response and to specifically investigate the role of IL-17A in this model system. Methods: Wild type (WT; C57BL/6) mice and IL-17A-defficient mice (IL-17A-/-; C57BL/6 genetic background) were challenged (intranasally) with 2 million viable Af conidia at weekly intervals. Specific antibody staining and flow cytometric analysis was used to identify, enumerate, and further characterize lung APC (dendritic cells, DC; macrophages, Mf; and basophils), and lymphocyte populations after 0, 2, 4, and 8 Af challenges. Clearance of Af from the lung was also assessed. Results: In WT mice, repetitive Af challenge increased the numbers of all APC (DC, Mf, and basophils) which peaked after 4 Af challenges. Transition from the Th2 phenotype to the Th1/Th17 phenotype (between 4 and 8 Af challenges) was associated with a decrease in DC but persistence of Mf. In contrast, DC and Mf numbers (but not basophils) were diminished in IL-17-/- mice. Expression of CD11b, CD80, and CD86 were similar between lung DC and Mf in lungs of AF-challenged WT mice and IL-17-/- mice. IL-17A-deficiency was associated with decreased numbers of CD4+ T cells and B cells (after 4 Af challenges) and a specific decrease in early lung Tregs and CD4+ T cells producing IL-10 but no changes in CD4+ T cells expressing IL-4 or IFN-g throughout the time course. Clearance of Af from the lung was improved in IL-17-/- mice. Conclusions: Repetitive pulmonary challenge with Af in mice results in a dynamic immune response characterized by alterations in both the number and phenotype of lung APC and T cells. Our results demonstrate that IL-17A mediates accumulation of lung DC and Mf at the peak of the allergic response to Af challenge yet also promotes early regulatory T cell responses and impairs clearance of the organism. Thus, therapies designed to enhance or diminish IL-17A levels will require careful investigation given the numerous effects of IL-17A on pulmonary immune responses.
2011

abstract No: 

C36

Full conference title: 

American Thoracic Society
    • ATS 2011