Functional IL-10 deficiency in the lung of cystic fibrosis (cftr(-/-)) and IL-10 knockout mice causes increased expression and function of B7 costimulatory molecules on alveolar macrophages.
Alveolar macrophages are poor APCs that only minimally express B7 costimulatory molecules. Because our previous data suggest that bronchial epithelial cells constitutively secrete IL-10, and IL-10 inhibits B7 expression in vitro, we hypothesized that this IL-10 is responsible for suppressing B7 expression on macrophages that enter the airways. Furthermore, because we have shown that cystic fibrosis (CF) lungs are deficient in IL-10, we hypothesized that bronchoalveolar macrophages (BALMs) from cystic fibrosis transmembrane conductance regulator (CFTR)(-/-) as well as IL-10(-/-) mice might express increased B7. Immunofluorescence for B7 was positive on BALMs from CF patients and CFTR(-/-) and IL-10(-/-) mice, but was negative on controls. FACS showed that 63.9% of BALMs from IL-10(-/-) mice were B7-1 positive, as were 67.4% of BALMs from CFTR(-/-) mice, whereas <7% of BALMs from wild-type controls were positive. Using BALMs to costimulate splenic T cells with anti-CD3 as a mitogen showed 9202 +/- 2107 cpm [(3)H]thymidine incorporation for BALMs from IL-10(-/-) mice and 4082 +/- 1036 cpm for BALMs from CFTR(-/-) mice, but <200 cpm with BALMs from either type of +/+ mouse. Treatment of CFTR(-/-) mice with recombinant mouse IL-10 reduced the B7 expression and costimulatory activity of the BALMs. These data suggest that the IL-10 secreted in the healthy lung may be responsible for the absence of B7 and poor costimulatory activity of BALMs and that reductions of pulmonary IL-10 in CF may enhance B7 expression and local immune responses.
Soltys
Jindrich
J
Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA.
Bonfield
Tracey
T
Chmiel
James
J
Berger
Melvin
M
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D051940:B7-2 Antigen; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000276:immunology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008168:Lung / Q000276:immunology; D008213:Lymphocyte Activation; D016676:Macrophages, Alveolar / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D016753:Interleukin-10