EBI3 deficiency leads to diminished T helper type 1 and increased T helper type 2 mediated airway inflammation

Abstract

Summary Despite extensive investigation of the signals required for development of T helper type 1 (Th1) and type 2 (Th2) immune responses, the mechanisms involved are still not well‐defined. A critical role for Epstein–Barr virus‐induced gene 3 (EBI3) in these responses has been proposed. EBI3, initially discovered as a transcriptionally activated gene in Epstein–Barr virus‐infected B lymphocytes, codes for a subunit of the cytokine interleukin‐27 (IL‐27). While initial studies suggested that it had an important role in promoting Th1 responses, subsequent studies have revealed that EBI3 receptor signalling influences a variety of immune cell types and can inhibit both Th1 and Th2 responses. In the present study, we evaluated EBI3−/− mice for their ability to mount both Th1‐mediated and Th2‐mediated airway inflammatory responses. The EBI3−/− mice sensitized by exposure to inhaled ovalbumin plus a high dose of lipopolysaccharide, which normally results in Th1 responses in wild‐type (WT) mice, instead developed Th2 type airway inflammation, with increased numbers of eosinophils. The EBI3−/− mice that were exposed to inhaled ovalbumin with a low dose of lipopolysaccharide, which induces Th2 responses in WT mice, showed a marked enhancement of these responses, with increased airway eosinophils, increased serum IgE levels and increased levels of Th2 cytokines (IL‐4, IL‐5 and IL‐13) in culture supernatants of mediastinal lymph node cells. Increased production of Th2 cytokines was also seen when naive CD4+ T cells from EBI3−/− mice were stimulated in vitro compared with cells from WT mice. These results provide the first evidence that EBI3 may play an inhibitory role in allergic asthma development.

The Immunobiology of Interleukin-27

“…During the induction of experimental asthma, endogenous IL-27 or treatment with IL-27 can limit Th2 responses and protect against lung inflammation, an effect that has been linked to the ability of invariant NKT cells to produce IL-27 (28, 124,208,209). This Th2-like asthma appears distinct from steroid-resistant asthma, which is associated with a Th1-like response and increased numbers of neutrophils.…”

The biology of interleukin-27 reveals unique pro- and anti-inflammatory functions in immunity

“…However, later studies showed that ebi3 À/À mice displayed a reduced Th1 and increased Th2 response in a murine asthma model [76]. When challenged with the intracellular pathogen L. major, the diminished Th1 response led to enhanced parasite numbers and increased lesions [77].…”

Upregulation of Interleukin-35 Subunits in Regulatory T Cells in a Murine Model of Allergic Rhinitis

“…Previous studies have demonstrated that some subunits of IL-12 cytokine members function not only as heterodimerized constituents of different cytokines but also independently of their heterodimer partners [26,27,28,29,30,31]. Ebi3 deficiency led to diminished Th1 responses and increased Th2-mediated airway inflammation in asthma [32]. Thus, we speculate that decreased Ebi3 mRNA expression in the nasal mucosa might also contribute to the development of a Th2 profile or allergic inflammation in AR, although this remains to be confirmed.…”