Summary In this study we examined the role IL-13 receptor alpha 1 (IL-13Rα1) plays in macrophage differentiation and function. The findings indicate that IL-13Rα1 is expressed on the M2 but not the M1 subset of macrophages and specifically heterodimerizes with the IL-4Rα chain to form a type II receptor, which controls the differentiation and function of these cells. Indeed, bone marrow (BM) cells from IL-13Rα1+/+ and IL-13Rα1−/− mice yield equivalent numbers of macrophages when cultured under M2 polarizing conditions. However, IL-13Rα1−/− BM cells yield a much higher number of macrophages than IL-13Rα1+/+ BM cells when the differentiation is carried out under M1-polarizing conditions. Further analyses indicated that macrophages that express IL-13Rα1 also display surface markers associated with an M2 phenotype. In addition, the IL-13Rα1+ macrophages were highly efficient in phagocytizing zymosan bioparticles both in vitro and in vivo, and supported differentiation of naïve T cells to a Th2 phenotype. Finally, when stimulated by IL-13, a cytokine that uses the heteroreceptor, the cells were able to phosphorylate STAT6 efficiently. These previously unrecognized findings indicate that IL-13Rα1 serves as a marker for M2 macrophages and the resulting heteroreceptor influences both their differentiation and function.

Neonatal immunity exhibits weak Th1 but excessive Th2 responses and the underlying mechanisms remain elusive. Here, we show that neonatal basophils readily produce IL-4, a cytokine that proved to be pivotal in shaping the programs of both lymphocyte subsets. Besides promoting Th2 programs, IL-4 is captured by the IL-4 heteroreceptor (IL-4Rα/IL-13Rα1) expressed on dendritic cells and instigates IL-12 down-regulation. Under these circumstances, differentiating Th1 cells up-regulate IL-13Rα1 leading to an unusual expression of the heteroreceptor which will serve as a death marker for these Th1 cells during re-challenge with antigen (Ag). The resulting Th1/Th2 imbalance impacts childhood immunity culminating in sensitivity to allergic reactions, susceptibility to microbial infection and perhaps poor efficacy of pediatric vaccines.

Upon exposure to Ag on the day of birth, neonatal mice mount balanced primary Th1 and Th2 responses with the former displaying up-regulated IL-13 receptor alpha 1 (IL-13Rα1) expression. This chain associates with IL-4Rα to form a heteroreceptor (IL-4Rα/IL-13Rα1) that marks the Th1 cells for death by IL-4 produced by Th2 cells during re-challenge with Ag, hence, the Th2 bias of murine neonatal immunity. The up-regulation of IL-13Rα1 on neonatal Th1 cells was due to the paucity of IL-12 in the neonatal environment. Herein, we show that by day 8 after birth, naïve splenic T cells are no longer susceptible to IL-13Rα1 up-regulation even when exposed to Ag within the neonatal environment. Furthermore, during the 8-day lapse, the naïve splenic T cells spontaneously and progressively up-regulate the IL-12Rβ2 chain, perhaps due to colonization by commensals which induce production of IL-12 by cells of the innate immune system such as dendritic cells. In fact, mature T cells from the thymus, a sterile environment not accessible to microbes, did not up-regulate IL-12Rβ2 and were unable to counter IL-13Rα1 up-regulation. Finally, the 8 day naïve T cells were able to differentiate into Th1 cells even independently of IL-12 but required the cytokine to counter up-regulation of IL-13Rα1. Thus, in neonatal mice, IL-12, which accumulates in the environment progressively, utilizes IL-12Rβ2 to counter IL-13Rα1 expression in addition to promoting Th1 differentiation.