CD4+ T helper cells engineered to produce latent TGF-β1 reverse allergen-induced airway hyperreactivity and inflammation
Gesine Hansen, Jennifer J. McIntire, V. Peter Yeung, Gerald Berry, G. Jeanette Thorbecke, Lizhen Chen, Rosemarie H. DeKruyff, Dale T. Umetsu
Gesine Hansen, Jennifer J. McIntire, V. Peter Yeung, Gerald Berry, G. Jeanette Thorbecke, Lizhen Chen, Rosemarie H. DeKruyff, Dale T. Umetsu
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CD4+ T helper cells engineered to produce latent TGF-β1 reverse allergen-induced airway hyperreactivity and inflammation

Abstract

T helper 2 (Th2) cells play a critical role in the pathogenesis of asthma, but the precise immunological mechanisms that inhibit Th2 cell function in vivo are not well understood. Using gene therapy, we demonstrated that ovalbumin-specific (OVA-specific) Th cells engineered to express latent TGF-β abolished airway hyperreactivity and airway inflammation induced by OVA-specific Th2 effector cells in SCID and BALB/c mice. These effects correlated with increased concentrations of active TGF-β in the bronchoalveolar lavage (BAL) fluid, demonstrating that latent TGF-β was activated in the inflammatory environment. In contrast, OVA-specific Th1 cells failed to inhibit airway hyperreactivity and inflammation in this system. The inhibitory effect of TGF-β–secreting Th cells was antigen-specific and was reversed by neutralization of TGF-β. Our results demonstrate that T cells secreting TGF-β in the respiratory mucosa can indeed regulate Th2-induced airway hyperreactivity and inflammation and suggest that TGF-β–producing T cells play an important regulatory role in asthma.

Authors

Gesine Hansen, Jennifer J. McIntire, V. Peter Yeung, Gerald Berry, G. Jeanette Thorbecke, Lizhen Chen, Rosemarie H. DeKruyff, Dale T. Umetsu

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Figure 5

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Lung histology of OVA- or KLH-immunized BALB/c mice after transfer of TG...
Lung histology of OVA- or KLH-immunized BALB/c mice after transfer of TGF-β–producing Th cells or Th1 cells. (a) Lung tissue from a control BALB/c mouse immunized with OVA intraperitoneally and intranasally, as described in Figure 3. Lung tissue was removed on day 11. An intense peribronchiolar mononuclear cell infiltrate is present, consisting of large numbers of eosinophils, lymphocytes, and a few neutrophils. H&E, ×300. Insert: The airway lumen is filled and expanded by thick mucus. The airway epithelium shows tall columnar cells exhibiting abundant cytoplasmic mucin. H&E, ×400. (b) Lung tissue from an OVA-immunized BALB/c mouse that received OVA-specific Th1 cells (2.5 × 106 cells/mouse) intravenously on day 7. Lung tissue was removed on day 11, 3 days after cell transfer. A dense peribronchiolar inflammatory infiltrate is present, consisting of lymphocytes, neutrophils, and few eosinophils. H&E, ×300. Insert: Lymphocytes are penetrating the airway epithelium and surrounding tissue spaces, but the airway lumen is free of mucus plugs. H&E, ×400. (c) Lung tissue from an OVA-immunized BALB/c mouse that received OVA-specific TGF-β–producing cells (2.5 × 106 cells/mouse) intravenously on day 7. H&E, ×300. Insert: There is a significant reduction of peribronchiolar inflammatory cells and a significant reduction in the number of eosinophils as compared with Figure 5, a and b. In addition, the airway epithelium is almost normal, and almost no mucus is present in the airway lumen. H&E, ×400. (d) The inflammatory response in lung tissue from a KLH-immunized BALB/c mouse is not reduced by transfer of OVA-specific TGF-β–producing cells (2.5 × 106 cells/mouse). Intense peribronchiolar mononuclear cell infiltrates are present, consisting of eosinophils and lymphocytes, and the airway lumen is filled and expanded by thick mucus, similar to that seen in Figure 5a. H&E, ×300. Insert: The airway epithelium shows tall columnar cells exhibiting abundant cytoplasmic mucin and inflammatory cells, including eosinophils and lymphocytes. H&E, ×400.