Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosis.
Hypersensitivity pneumonitis is an environmental lung disease characterized by a diffuse mononuclear cell infiltrate in the lung that can progress to pulmonary fibrosis with chronic exposure to an inhaled Ag. Using a well-established murine model of hypersensitivity pneumonitis, we repeatedly exposed C57BL/6 mice to Saccharopolyspora rectivirgula to investigate whether T cells are required for lung fibrosis. In the absence of alphabeta T cells, TCRbeta(-/-) mice exposed to S. rectivirgula for 4 wk had markedly decreased mononuclear infiltrates and collagen deposition in the lung compared with wild-type C57BL/6 mice. In contrast to CD8(+) T cells, adoptive transfer of CD4(+) T cells reconstituted the S. rectivirgula-induced inflammatory and fibrotic response, suggesting that the CD4(+) T cell represents the critical alphabeta T cell subset. Cytokine analysis of lung homogenates at various time points after S. rectivirgula exposure failed to identify a predominant Th1 or Th2 phenotype. Conversely, IL-17 was found in the lung at increasing concentrations with continued exposure to S. rectivirgula. Intracellular cytokine staining revealed that 14% of CD4(+) T cells from the lung of mice treated with S. rectivirgula expressed IL-17A. In the absence of IL-17 receptor signaling, Il17ra(-/-) mice had significantly decreased lung inflammation and fibrosis compared with wild-type C57BL/6 mice. These data are the first to demonstrate an important role for Th17-polarized CD4(+) T lymphocytes in the immune response directed against S. rectivirgula in this murine model of hypersensitivity pneumonitis and pulmonary fibrosis.
Simonian
Philip L
PL
Department of Medicine, University of Colorado Denver, Denver, CO 80262, USA. philip.simonian@ucdenver.edu
Roark
Christina L
CL
Wehrmann
Fabian
F
Lanham
Allison K
AK
Diaz del Valle
Fernando
F
Born
Willi K
WK
O'Brien
Rebecca L
RL
Fontenot
Andrew P
AP
D019264:Adoptive Transfer; D000542:Alveolitis, Extrinsic Allergic / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D000818:Animals; D004195:Disease Models, Animal; D005203:Farmer's Lung / Q000235:genetics / Q000276:immunology / Q000628:therapy; D005260:Female; D016130:Immunophenotyping; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency / Q000235:genetics; D016930:Saccharopolyspora / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000382:microbiology / Q000637:transplantation
C098680:Il17a protein, mouse; D020381:Interleukin-17; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta