Th type 1-stimulating activity of lung macrophages inhibits Th2-mediated allergic airway inflammation by an IFN-gamma-dependent mechanism.
In the mucosal immune system, resident dendritic cells are specialized for priming Th2-polarized immunity, whereas the Ag-presenting activity of macrophages has been linked with the development of Th1 phenotype. As an immune switch toward Th1 can protect against Th2-mediated allergic response, this study investigated the capacity of lung macrophages to stimulate Th1 responses during the secondary exposure to inhaled allergen, thereby suppressing Th2-mediated allergic airway inflammation in a murine model of allergic asthma. Following airway macrophage depletion in OVA-sensitized mice, lung T cells defaulted to a phenotype that produced less Th1 (IFN-gamma) and more Th2 (IL-4 and IL-5) cytokines, leading to more severe airway hyperreactivity and inflammation after intranasal Ag challenge. After OVA pulsing and adoptive transfer, lung macrophages selectively promoted a Th1 response in Ag-sensitized recipients and did not induce pulmonary eosinophilia. By contrast, OVA pulsing and adoptive transfer of a lung cell preparation, consisting of dendritic cells, B cells, and macrophages, promoted a Th2 response with an associated inflammatory response that was suppressed when macrophages were present and pretreated with IFN-gamma, but exacerbated when macrophages were depleted before IFN-gamma treatment. In addition, Th1-promoting activity of lung macrophages was not related to the autocrine production of IL-12p40. These results suggest that the Th1-promoting APC activity may be an inherent property of the lung macrophage population, and may play an important role, upon stimulation by IFN-gamma, in antagonizing an ongoing Th2 immunity and Th2-dependent allergic responses.
Tang
C
C
Asthma Research Group, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Inman
M D
MD
van Rooijen
N
N
Yang
P
P
Shen
H
H
Matsumoto
K
K
O'Byrne
P M
PM
D000281:Administration, Intranasal; D019264:Adoptive Transfer; D000485:Allergens / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D004002:Clodronic Acid / Q000008:administration & dosage / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004802:Eosinophilia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D005260:Female; D016130:Immunophenotyping; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D007371:Interferon-gamma / Q000502:physiology*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000502:physiology; D007970:Leukopenia / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology; D008081:Liposomes / Q000008:administration & dosage / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D000485:Allergens; D016207:Cytokines; D008081:Liposomes; D004002:Clodronic Acid; D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin