Fas-positive T cells regulate the resolution of airway inflammation in a murine model of asthma

Abstract

Persistent airway inflammation, mucus production, and airway hyperreactivity are the major contributors to the frequency and severity of asthma. Why lung inflammation persists in asthmatics remains unclear. It has been proposed that Fas-mediated apoptosis of inflammatory cells is a fundamental mechanism involved in the resolution of eosinophilic airway inflammation. Because infiltrating eosinophils are highly sensitive to Fas-mediated apoptosis, it has been presumed that direct ligation of Fas on eosinophils is involved. Here, we utilize adoptive transfers of T cells to demonstrate that the delayed resolution of eosinophilia in Fas-deficient mice is a downstream effect of Fas deficiency on T cells, not eosinophils. Interestingly, the mice that received Fas-deficient T cells, but not the controls, developed a persistent phase of inflammation that failed to resolve even 6 wk after the last challenge. This persistent phase correlated with decreased interferon (IFN)γ production by Fas-deficient T cells and could be reproduced with adoptive transfer of IFNγ-deficient T cells. These data demonstrate that Fas deficiency on T cells is sufficient for the development of long-term allergic airway disease in mice and implies that deregulation of death receptors such as Fas on human T cells could be an important factor in the development and/or chronic nature of asthma.

Fas Ligand Expression on T Cells Is Sufficient to Prevent Prolonged Airway Inflammation in a Murine Model of Asthma

“…To investigate how Fas-FasL interactions occur and regulate the resolution of airway inflammation in vivo, we used a previously described murine model of allergic airway disease and mice with abnormalities in the FasL signaling pathway (8,21). We found that FasL deficiency (Gld) led to a delayed resolution of airway inflammation similar to our previous observations.…”

“…Duez and colleagues (7) have shown that Fas deficiency delays the resolution of airway hyperresponsiveness (AHR) after allergen sensitization and challenge. Fas-deficient mice have a delayed resolution of airway inflammation, and mice with Fas deficiency only on T cells developed a prolonged phase of airway inflammation, mucus production, and airway hyperreactivity (8). This prolonged airway inflammation phase correlated with decreased IFN-g production by Fas-deficient T cells.…”

“…Sensitization and challenge were described previously (8,21). Briefly, at Day 214, mice were immunized by intraperitoneal injection of inactivated Schistosoma mansoni eggs, which induce a strong T helper cell type (Th) 2 response in the absence of active infection.…”

Resolvin E1 regulates interleukin 23, interferon-γ and lipoxin A4 to promote the resolution of allergic airway inflammation

“…IFN-γ can contribute to resolution by upregulating Fas (CD95) expression on lymphocytes to increase their rate of apoptosis 41 . Mice lacking IFN-γ or Fas exhibit defective resolution of inflammation in experimental models of asthma 42,43 . As an IFN-γ-neutralizing antibody partially blocked RvE1-mediated resolution, IFN-γ is important for resolution of airway inflammation in this setting.…”

Human Peripheral Blood T Regulatory Cells (Tregs), Functionally Primed CCR4+ Tregs and Unprimed CCR4− Tregs, Regulate Effector T Cells Using FasL

“…Fas/FasL (CD95/CD95L) signaling plays a major role in the physiological regulation of T cell homeostasis (38), and Fas deficiency on T cells has been associated with the development of long-term allergic airway disease in mice (51). However, FasL/Fas has never been associated with the function of Tregs, including the GZ-A-and GZ-B-expressing Tr1 (28).…”