Chronic follicular bronchiolitis requires antigen-specific regulatory T cell control to prevent fatal disease progression. J Immunol 2013 Dec 01;191(11):5460-76
Date
10/29/2013Pubmed ID
24163409Pubmed Central ID
PMC3893829DOI
10.4049/jimmunol.1301576Scopus ID
2-s2.0-84888363726 (requires institutional sign-in at Scopus site) 4 CitationsAbstract
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.
Author List
Schmitt EG, Haribhai D, Jeschke JC, Co DO, Ziegelbauer J, Yan K, Iwakura Y, Mishra MK, Simpson P, Salzman NH, Williams CBAuthors
Nita H. Salzman MD, PhD Director, Professor in the Pediatrics department at Medical College of WisconsinPippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Calvin B. Williams MD, PhD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Ke Yan PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsB-Lymphocytes
Bronchioles
Bronchiolitis
Cell Movement
Cells, Cultured
Chronic Disease
Disease Progression
Hemoglobins
Humans
Interferon-gamma
Interleukin-17
Lymphocyte Depletion
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Muramidase
Organ Specificity
Promoter Regions, Genetic
Receptors, Antigen, T-Cell
Recombinant Fusion Proteins
T-Lymphocyte Subsets
T-Lymphocytes, Regulatory
Uteroglobin