IL-4/IL-13 Heteroreceptor Influences Th17 Cell Conversion and Sensitivity to Treg Suppression to Restrain Experimental Allergic Encephalomyelitis

摘要

IL-4 and IL-13 have been defined as anti-inflammatory cytokines which can counter myelin-reactive T cells and modulate experimental allergic encephalomyelitis (EAE). However, it is not known whether endogenous IL-4 and IL-13 contribute to the maintenance of peripheral tolerance and whether their function is coordinated with T regulatory cells (Tregs). Here, we utilized mice in which the common cytokine receptor for IL-4 and IL-13, namely the IL-4Rα/IL-13Rα1 heteroreceptor (HR), is compromised and determined whether the lack of signaling by endogenous IL-4 and IL-13 through the HR influences the function of effector Th1 and Th17 cells in a Treg-dependent fashion. The findings indicate that mice-deficient for the HR (13R^-/-) are more susceptible to EAE than mice sufficient for the HR (13R^+/+) and develop early onset and more severe disease. Moreover, Th17 cells from 13R^-/- mice had reduced ability to convert to Th1 cells and displayed reduced sensitivity to suppression by Tregs relative to Th17 effectors from 13R^+/+ mice. These observations suggest that IL-4 and IL-13 likely operate through the HR and influence Th17 cells to convert to Th1 cells and to acquire increased sensitivity to suppression leading to control of immune-mediated central nervous system inflammation. These previously unrecognized findings shed light on the intricacies underlying the contribution of cytokines to peripheral tolerance and control of autoimmunity.