IL-10 Mediates Resistance to Adoptive Transfer Experimental Autoimmune Encephalomyelitis in MyD88−/− Mice

Abstract

MyD88 is an adaptor molecule that functions in the innate signaling induced by proinflammatory adjuvants that interact with TLRs. Mice lacking MyD88, for example, resist active experimental autoimmune encephalomyelitis (EAE) induced by immunization with an encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide in CFA. We reasoned that MyD88−/− mice, nevertheless, should be susceptible to EAE mediated by adoptive transfer of activated encephalitogenic T cell lines, which do not require adjuvant signaling for their effector functions. We now report, however, that mice lacking MyD88 also resist adoptive EAE mediated by an anti-MOG T cell line that is strongly encephalitogenic in wild-type (WT) mice. The transferred anti-MOG T cells proliferated, secreted INF-γ, and migrated to the CNS in the MyD88−/− mice, as they did in WT mice, but inflammatory infiltrates did not progress and clinical EAE did not develop. The resistance of the MyD88−/− mice to adoptive EAE mediated by the otherwise encephalitogenic T cells was found to result from the secretion of IL-10 by recipient T cells of two different specificities: those specific for MOG and those responding to the T cell clone itself—both anticlonotypic and antiergotypic T regulators were detected. IL-10–producing anti-MOG T cells isolated from immunized MyD88−/− mice suppressed the induction of active EAE in WT recipients. Moreover, the absence of IL-10 production in MyD88/IL-10 double-knockout mice rendered the mice susceptible to adoptive transfer of EAE. Thus, MyD88 signaling appears to be a key factor in determining the cytokine phenotype of T cells involved in autoimmune inflammation and regulation.

Multiple Checkpoint Breach of B Cell Tolerance in Rasgrp1-Deficient Mice

“…Both microbial and self-molecules can serve as TLR agonists, though the relative importance of these agonists in disease in vivo is unknown. In addition, mice lacking MyD88 (the common adaptor molecule involved in TLR signaling) are less susceptible to breaches of B cell tolerance and autoantibody production in other mouse models (34)(35)(36)(37)(38)(39) (44,45). The importance of T follicular helper cells has not been established in lymphopenic autoimmune environments, though they are considered important in other autoimmune models (46).…”

Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential

“…The resistance of MyD88 KO mice to EAE was determined to be dependent, in part, on TLR9 signaling, since EAE onset was delayed in animals where TLR9 was specifically deleted within the CNS compartment. In addition to resistance to active MOG-induced EAE, MyD88 KO mice were also refractory to EAE following the adoptive transfer of encephalitogenic MOG-specific T cells, the latter of which bypasses TLR adjuvant signaling [203]. The resistance of MyD88 KO mice during adoptive transfer EAE depended on IL-10 induction, since susceptibility to adoptive transfer EAE was restored in MyD88/IL-10 double KO mice.…”

“…The resistance of MyD88 KO mice during adoptive transfer EAE depended on IL-10 induction, since susceptibility to adoptive transfer EAE was restored in MyD88/IL-10 double KO mice. Similarly, adoptive transfer of IL-10 secreting MOG-specific T cells from MyD88 KO mice was capable of suppressing disease in WT animals, indicating a direct role for MyD88 signaling in dictating T cell cytokine phenotype [203]. Based on the available evidence, MyD88 signaling may represent a possible target for future MS therapies.…”

Regulatory role of resveratrol on Th17 in autoimmune disease

“…Mice rendered genetically deficient in IL-10 developed more severe EAE [133,134] while mice transgenically manipulated to express IL-10 under the Class II MHC promoter are resistant to development of EAE [135]. Interestingly, MyD88−/− mice, which are resistant to development of active EAE, are also resistant to passive EAE with encephalitogenic T cells of wt mice due to high IL-10 secretion by recipient T cells after passive transfer [136]. In addition, day 10 EAE splenic T cell from SJL/J mice, which are susceptible to EAE, produce lower levels of IL-10 than those of H-2 congenic B10.S mice which are resistant to EAE [137].…”