title: Chronic follicular bronchiolitis requires antigen-specific regulatory T cell control to prevent fatal disease progression.
abstract: To study regulatory T (Treg) cell control of chronic autoimmunity in a lymphoreplete host, we created and characterized a new model of autoimmune lung inflammation that targets the medium and small airways. We generated transgenic mice that express a chimeric membrane protein consisting of hen egg lysozyme and a hemoglobin epitope tag under the control of the Clara cell secretory protein promoter, which largely limited transgene expression to the respiratory bronchioles. When Clara cell secretory protein-membrane hen egg lysozyme/hemoglobin transgenic mice were crossed to N3.L2 TCR transgenic mice that recognize the hemoglobin epitope, the bigenic progeny developed dense, pseudo-follicular lymphocytic peribronchiolar infiltrates that resembled the histological pattern of follicular bronchiolitis. Aggregates of activated IFN-γ- and IL-17A-secreting CD4(+) T cells as well as B cells surrounded the airways. Lung pathology was similar in Ifng(-/-) and Il17a(-/-) mice, indicating that either cytokine is sufficient to establish chronic disease. A large number of Ag-specific Treg cells accumulated in the lesions, and Treg cell depletion in the affected mice led to an interstitial spread of the disease that ultimately proved fatal. Thus, Treg cells act to restrain autoimmune responses, resulting in an organized and controlled chronic pathological process rather than a progressive disease.
authors.affiliation: Section of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Erica G
authors.initials: EG
authors.lastname: Schmitt
authors.forename: Dipica
authors.initials: D
authors.lastname: Haribhai
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Jeschke
authors.forename: Dominic O
authors.initials: DO
authors.lastname: Co
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ziegelbauer
authors.forename: Ke
authors.initials: K
authors.lastname: Yan
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Mishra
authors.forename: Pippa
authors.initials: P
authors.lastname: Simpson
authors.forename: Nita H
authors.initials: NH
authors.lastname: Salzman
authors.forename: Calvin B
authors.initials: CB
authors.lastname: Williams
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D055745:Bronchioles / Q000378:metabolism*; D001988:Bronchiolitis / Q000276:immunology*; D002465:Cell Movement; D002478:Cells, Cultured; D002908:Chronic Disease; D018450:Disease Progression; D006454:Hemoglobins / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014598:Uteroglobin / Q000235:genetics
chemical_list: D006454:Hemoglobins; D020381:Interleukin-17; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma; D014598:Uteroglobin; C421864:hen egg lysozyme; D009113:Muramidase