Absence of the Common Gamma Chain (γ(c)), a Critical Component of the Type I IL-4 Receptor, Increases the Severity of Allergic Lung Inflammation

The T(H)2 cytokines, IL-4 and IL-13, play critical roles in inducing allergic lung inflammation and drive the alternative activation of macrophages (AAM). Although both cytokines share receptor subunits, IL-4 and IL-13 have differential roles in asthma pathogenesis: IL-4 regulates T(H)2 cell differentiation, while IL-13 regulates airway hyperreactivity and mucus production. Aside from controlling T(H)2 differentiation, the unique contribution of IL-4 signaling via the Type I receptor in airway inflammation remains unclear. Therefore, we analyzed responses in mice deficient in gamma c (γ(c)) to elucidate the role of the Type I IL-4 receptor. OVA primed CD4(+) OT-II T cells were adoptively transferred into RAG2(−/−) and γ(c) (−/−) mice and allergic lung disease was induced. Both γ(c) (−/−) and γ(c)xRAG2(−/−) mice developed increased pulmonary inflammation and eosinophilia upon OVA challenge, compared to RAG2(−/−) mice. Characteristic AAM proteins FIZZ1 and YM1 were expressed in lung epithelial cells in both mouse strains, but greater numbers of FIZZ1+ or YM1+ airways were present in γ(c) (−/−) mice. Absence of γ(c) in macrophages, however, resulted in reduced YM1 expression. We observed higher T(H)2 cytokine levels in the BAL and an altered DC phenotype in the γ(c) (−/−) recipient mice suggesting the potential for dysregulated T cell and dendritic cell (DC) activation in the γ(c-)deficient environment. These results demonstrate that in absence of the Type I IL-4R, the Type II R can mediate allergic responses in the presence of T(H)2 effectors. However, the Type I R regulates AAM protein expression in macrophages.