Non-classical MHC I-E negatively regulates macrophage activation and Th17 cell development in NOD mice

TL;DR

This study shows that a non-classical MHC II molecule, I-E, reduces inflammation and prevents diabetes in mice by suppressing harmful immune cells.

Contribution

The study reveals a new regulatory role of non-classical MHC II molecules in controlling macrophage activation and Th17 cell development.

Findings

Transgenic I-E expression reduces Th17 cells in the thymus and pancreatic lymph nodes of NOD mice.

I-E expression decreases macrophage activation and IL-6 production.

I-E impairs TLR4 signaling and reduces classical MHC II expression.

Abstract

Transgenic expression of I-E molecules prevents diabetes in NOD mice. So far, the precise role of these non-classical MHC II molecules remains elusive. Here, we showed that transgenic expression of I-Ek alpha 16 molecule in NOD mice selectively reduced Th17 cells in the thymus and pancreatic draining lymph nodes. The reduction in Th17 cells was associated with both attenuated IL-6 production and decreased activation of macrophages. Mechanistically, transgenic expression of the I-E molecule diminished expression of intracellular classical MHC II molecule and led to impaired TLR4-mediated signaling. In contrast to classical MHC II molecule, this non-classical MHC II molecule negatively regulates the inflammatory responses of macrophages. Altogether, our study reveals a novel regulatory role of I-E molecules in modulating inflammatory immune responses.

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