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γδ T cells protect against lung fibrosis via IL-22
Philip L Simonian1, Fabian Wehrmann, Christina L Roark
1Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
Abstract:
Inflammation-induced pulmonary fibrosis (PF) leads to irreversible loss of lung function and is a predictor of mortality in numerous lung diseases. Why some subjects with lung inflammation but not others develop PF is unclear. In a mouse model of hypersensitivity pneumonitis that progresses to lung fibrosis upon repeated exposure to the ubiquitous microorganism Bacillus subtilis, γδ T cells expand in the lung and inhibit collagen deposition. We show that a subset of these γδ cells represents the predominant source of the Th17 cytokine IL-22 in this model. Preventing expression of IL-22, either by mutating the aryl hydrocarbon receptor (AhR) or inhibiting AhR signaling, accelerated lung fibrosis. Direct blockade of IL-22 also enhanced collagen deposition in the lung, whereas administration of recombinant IL-22 inhibited lung fibrosis. Moreover, the presence of protective γδ T cells and IL-22 diminished recruitment of CD4(+) T cells to lung. These data reveal a protective pathway that involves the inhibition of αβ T cells by regulatory IL-22-secreting γδ T cells.
Insights
Regulatory gamma delta T cells and IL-22 protect against pulmonary fibrosis by inhibiting alpha beta T cells. This discovery offers new insights into preventing lung function loss in inflammatory lung diseases.
Area of Science:
- Immunology
- Pulmonary Medicine
- Cell Biology
Background:
- Pulmonary fibrosis (PF) causes irreversible lung damage and mortality.
- The mechanisms underlying PF development in inflammatory lung diseases remain unclear.
- Identifying protective pathways is crucial for therapeutic development.
Purpose of the Study:
- To investigate the role of gamma delta (γδ) T cells and Interleukin-22 (IL-22) in a mouse model of inflammation-induced pulmonary fibrosis.
- To elucidate the signaling pathways involved in γδ T cell-mediated protection against fibrosis.
Main Methods:
- Utilized a mouse model of hypersensitivity pneumonitis induced by Bacillus subtilis exposure.
- Investigated the function of γδ T cells and IL-22 by genetic manipulation (aryl hydrocarbon receptor mutation) and pharmacological inhibition/administration.
- Assessed collagen deposition and T cell recruitment in lung tissue.
Main Results:
- A subset of γδ T cells was identified as the primary source of IL-22 in the fibrotic lung.
- Inhibition of IL-22 or its signaling pathway (via aryl hydrocarbon receptor) exacerbated lung fibrosis.
- Administration of IL-22 inhibited collagen deposition and reduced CD4(+) T cell recruitment.
- Regulatory γδ T cells secreting IL-22 were shown to inhibit αβ T cells.
Conclusions:
- γδ T cells secreting IL-22 represent a key protective mechanism against pulmonary fibrosis.
- IL-22 plays a critical role in mitigating lung fibrosis by modulating T cell responses.
- This pathway highlights a novel therapeutic target for preventing or treating pulmonary fibrosis.
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