Abstract
Fas (CD95/APO-1) and its ligand (FasL/CD95L) promote the resolution of type 2 lung inflammation and eosinophilia. We previously found that Fas-deficiency on T cells, but not eosinophils, delayed resolution of inflammation. However, Fas can signal both cell death and have a positive signaling function that can actually activate cells. In this study, we investigated whether Fas-induced death or Fas-activated signaling pathways promote resolution of allergic lung inflammation. By increasing T cell survival through two Fas-independent pathways, using Bim-deficient T cells or Bcl-xL overexpressing T cells, no differences in resolution of Th2-mediated inflammation was observed. Furthermore, Th2 cells were inherently resistant to Fas-mediated apoptosis and preferentially signaled through non-apoptotic pathways following FasL treatment. Utilizing Fas-mutant mice deficient in apoptotic but sufficient for non-apoptotic Fas signaling pathways, we demonstrate that non-apoptotic Fas signaling in T cells drives resolution of Th2-mediated airway inflammation. Our findings reveal a previously unknown role for non-apoptotic Fas signaling on Th2 cells in the induction of resolution of type 2 inflammation.
Highlights
Atopic asthma is supported by a type 2 immune response mediated by expansion of T helper type 2 (Th2) cells reactive against ordinarily innocuous allergens [1, 2]
To test the possibility that these findings were due to changes in T cell survival, we examined whether increasing T cell survival through Fas-independent mechanisms could lead to delays in the resolution of inflammation [23]
Adoptive transfer of Bim−/− T cells into Rag−/− mice (Bim−/−>Rag−/−) followed by sensitization and challenge resulted in a dramatic increase in the number of T cells having infiltrated into the lungs of mice at all-time points examined (Figures 1A,B)
Summary
Atopic asthma is supported by a type 2 immune response mediated by expansion of T helper type 2 (Th2) cells reactive against ordinarily innocuous allergens [1, 2]. While increased Th2 cell recruitment to the lungs drives features of allergic responses, it is possible that defective resolution of type 2 responses in asthmatics could account for prolonged airway disease and contribute to disease phenotypes. The observation that those who suffer from intermittent or persistent asthma have elevated numbers of antigen-experienced T cells and eosinophils in sputum samples, even when samples are collected between exacerbations, supports the premise that asthma may be, in part, driven by defects in resolution of Th2 responses [3]. Expanding on the known mechanisms involved in resolving established inflammation in the airways may complement current therapeutic approaches that aim to inhibit the initiation of allergic inflammation, and instead focus on developing methods to end chronic inflammation.
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