1. ¹School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand
2. ²Department of Obstetrics and Gynaecology, Wellington School of Medicine, University of Otago, Wellington, New Zealand
3. ³The International Centre for Genetic Engineering and Biotechnology, University of Cape Town, Cape Town, South Africa

Correspondence: Dr AC La Flamme, School of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand. E-mail: anne.laflamme@vuw.ac.nz

Received 23 February 2009; Revised 28 April 2009; Accepted 1 May 2009; Published online 2 June 2009.

Abstract

The administration of Th2 cytokines or immune deviation to a Th2 phenotypic response has been shown to protect against the autoimmune pathology of experimental autoimmune encephalomyelitis (EAE). To better understand the function of Th2 cytokines in the induction stage of EAE in the absence of an overt Th2 response, we immunized IL-4 receptor alpha-deficient (IL-4R^-/-) mice, which are unable to respond to either IL-4 or IL-13. Contrary to expectations, mice lacking IL-4R had a lower incidence of EAE and a delayed onset compared to WT BALB/c mice; however, this delay did not correlate to an alteration in the Th1/Th17 cytokine balance. Instead, IL-4R-responsive macrophages were essential promoters of disease as macrophage-specific IL-4R-deficient (LysM^creIL-4R^-/lox) mice were protected from EAE. The protection afforded by IL-4R-deficiency was not due to IL-10-, IFN--, NO- or IDO-mediated suppression of T-cell responses but was dependent upon the presence of regulatory T cells (Tregs). This investigation highlights the importance of macrophages and Tregs in regulating central nervous system inflammation and demonstrates that macrophages activated in the absence of Th2 cytokines can promote disease suppression by Tregs.