EAE tolerance induction with Hsp70-peptide complexes depends on H60 and NKG2D activity

Area of Science:

• Immunology
• Neuroscience
• Molecular Biology

Background:

• Inflammation can trigger stress responses that limit immune activity.
• Heat shock protein 70-peptide complexes (Hsp70-pc) previously shown to induce NK-cell-dependent tolerance in experimental autoimmune encephalomyelitis (EAE).

Purpose of the Study:

• To investigate the molecular mechanisms underlying Hsp70-pc-induced EAE tolerance.
• To determine the role of MHC class I-related glycoprotein H60 and its receptor NKG2D in this process.

Main Methods:

• Utilized SJL/J and C57BL/6 mouse models of EAE.
• Administered Hsp70-pc and employed antibody blockade of H60 and NKG2D.
• Analyzed H60 expression on immune cells and assessed T cell reactivity to myelin proteolipid protein (PLP).
• Investigated dendritic cell function and NK cell activity.

Main Results:

• Hsp70-pc significantly upregulated H60 expression in SJL/J mice, crucial for EAE tolerance.
• Antibody blockade of H60 or NKG2D reversed Hsp70-pc-induced EAE tolerance.
• H60 was not expressed in C57BL/6 mice, and Hsp70-pc did not induce tolerance.
• NK cell-mediated tolerance involved modulation of dendritic cells, reducing T cell reactivity to PLP.
• Direct killing of H60+ PLP-reactive cells was not implicated in tolerance induction.

Conclusions:

• Hsp70-pc-induced EAE tolerance is mediated by NK cells through the induction of H60 ligand and its interaction with the NKG2D receptor.
• This interaction alters dendritic cell function, leading to enhanced death of antigen-reactive cells and diminished T cell responses.
• The findings highlight a novel pathway for immune tolerance in neuroinflammation.