Activating Receptors for Self-MHC Class I Enhance Effector Functions and Memory Differentiation of NK Cells during Mouse Cytomegalovirus Infection

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Natural killer (NK) cells are important in host defense against pathogens, and they can subsequently differentiate into memory NK cells. The Ly49 and KIR gene families in rodents and humans encode both inhibitory and activating receptors for MHC class I. The physiological role of activating KIR or Ly49 receptors that recognize self-MHC class I during immune response to viral infections is unknown. Here, we address how the activating Ly49D receptor impacts the NK cell response to mouse cytomegalovirus (MCMV) infection by comparing the activation and differentiation of Ly49D-bearing NK cells in mice lacking or expressing H-2Dd, the cognate MHC class I ligand of Ly49D. After MCMV infection, Ly49D augmented IFN-γ production by MCMV-specific Ly49H+ NK cells and preferentially promoted the generation of memory Ly49H+ NK cells. Thus, activating receptors for self-MHC class I modulate the differentiation of MCMV-specific NK cells and are beneficial for host defense against MCMV infection.

The physiological relevance of activating receptors on NK cells that recognize polymorphic self-MHC I antigens is unclear. Nabekura and Lanier show that NK cells with activating self-MHC receptors are hypo-responsive at steady-state, and during viral infection, these receptors augment cytokine production and promote the survival of long-lived memory NK cells.

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