Role of NKG2D in viral clearance from brain during infection with the Theiler’s murine encephalomyelitis virus (TMEV)

Abstract

Stress-dependent regulation of the immune response is a general repair and maintenance system. Members of the MHC class I superfamily serve as indicators of cellular stress. Nonclassical class I molecules such as H60, MULT-1 and the RAE-1 family are generally absent in normal tissues. We found that intracerebral infection with TMEV upregulated expression of these stress-response molecules in the brain at timepoints that coincided with the control of viral load. Moreover, we found that about 50% of the brain- infiltrating cytotoxic T cells (CTLs) specific for the TMEV peptide VP2121–130 were positive for the NKG2D activating receptor at 7 days postinfection. NKG2D binds to RAE-1, H60, and MULT-1 and costimulates CTLs. When we blocked NKG2D using the CX5 function blocking antibody we found a significant increase in viral load in the brain. Therefore, we hypothesize that cellular stress associated with viral infection induces NKG2D ligand expression on target cells that in turn costimulates NKG2D-bearing VP2-specific CTLs to promote viral clearance. Our study may ultimately impact the health of people at risk from encephalitis and neurologic complications associated with picornaviral infections and may provide new ways to promote viral clearance in individuals suffering from persistent virus infections of the brain.