Recognition of a virus-encoded ligand by a natural killer cell activation receptor

TLDR

NK cells express activation receptors that recognize MHC class I‑like molecules, and the Ly49H receptor confers resistance to murine cytomegalovirus, yet its ligand was unknown. The study aimed to identify the Ly49H ligand and explore other viral ORFs with MHC‑like folds that might mediate immune evasion. Using heterologous reporter cells and a bioinformatics screen of the MCMV genome, the authors identified the viral protein m157 as a Ly49H ligand. m157 activates Ly49H, inducing NK‑cell cytotoxicity and cytokine/chemokine production.

Abstract

Natural killer (NK) cells express inhibitory and activation receptors that recognize MHC class I-like molecules on target cells. These receptors may be involved in the critical role of NK cells in controlling initial phases of certain viral infections. Indeed, the Ly49H NK cell activation receptor confers in vivo genetic resistance to murine cytomegalovirus (MCMV) infections, but its ligand was previously unknown. Herein, we use heterologous reporter cells to demonstrate that Ly49H recognizes MCMV-infected cells and a ligand encoded by MCMV itself. Exploiting a bioinformatics approach to the MCMV genome, we find at least 11 ORFs for molecules with previously unrecognized features of predicted MHC-like folds and limited MHC sequence homology. We identify one of these, m157, as the ligand for Ly49H. m157 triggers Ly49H-mediated cytotoxicity, and cytokine and chemokine production by freshly isolated NK cells. We hypothesize that the other ORFs with predicted MHC-like folds may be involved in immune evasion or interactions with other NK cell receptors.