Skip to main content
editorial
. 2019 Oct;61(4):414–416. doi: 10.1165/rcmb.2019-0118ED

Figure 1.

Figure 1.

T-bet (T-box expressed in T cells) deficiency leads to exaggerated emphysema development in porcine pancreatic elastase (PPE)-treated mice. When challenged with PPE delivered by the intratracheal route, T-bet−/− mice developed exaggerated emphysema compared with wild-type mice. The exaggerated emphysema phenotype in the PPE-treated T-bet−/− mice was associated with enhanced early recruitment of neutrophils and lymphocytes into their lungs. PPE-treated T-bet−/− mice had higher IL-17– and RAR-related orphan receptor gamma (RORγt)-expressing CD4+ T cells, and increased expression of Il-6 and Il-17 in their lungs. Delivering neutralizing antibodies to Il-6R and Il-17 ameliorated the increased emphysema development in PPE-treated T-bet−/− mice, indicating that increased Il-6 and Il-17 signaling is required for the exaggerated PPE-induced emphysema in T-bet−/− mice. It is likely that T-bet deficiency in both macrophages and CD4+ T cells contributes to the phenotype of the mice. T-bet deficiency in CD4+ T cells increases Il-17 production in the lungs by polarizing the T cells toward a T-helper cell type 17 (Th17) phenotype, consistent with the known activity of T-bet in suppressing the development of Th17 cells by inhibiting transcription of Rorc, which encodes the transcription factor RORγt, which drives Th17 differentiation. Direct interactions between CD4+ T cells and macrophages may also contribute to Th17 polarization, as T-bet deficiency in macrophages increases the production of Il-6 and Tgf-β, which increase the differentiation of Th17 cells, and also the release of other proinflammatory mediators. The increased levels of Il-17 in the lung activate epithelial cells to release chemokines for polymorphonuclear neutrophils (PMNs) and monocytes, thereby increasing the recruitment of PMNs and monocytes into the lung, and their release of oxidants, serine proteinases, and matrix metalloproteinases (MMPs) that injure the alveolar walls. T-bet deficiency in macrophages may also promote an exaggerated innate immune response by increasing macrophage expression of Cxcl-2, which stimulates PMN recruitment, and Tnf-α, which activates macrophages to release MMPs and oxidants that also contribute to emphysema development. Ab = antibody; Tgf = transforming growth factor.