Stress Signals Activate Natural Killer Cells

The mechanisms that regulate NK cell function as a first line of defense against infection and transformation have exceeded our expectations in terms of their sophistication and complexity. Quiescent, circulating NK cells can be activated by either soluble mediators, such as interferons and cytokines, or by direct cell–cell contact. Activation occurs during contact not only when NK cells sense the loss of MHC class I expression on the surface of other cells but also with cells that have undergone other alterations induced by infection or cellular stress. Notably, expression of ligands for receptor NKG2D induced by stress or transformation results in activation signals that can overcome the inhibition mediated by MHC class I–specific receptors (1– 4). Yet another mode of NK cell activation upon cellular stress is described in this issue by Michaëlsson et al. (5). Replacement of a peptide on an MHC class I molecule by a peptide released from a heat shock protein prevents recognition by an NK cell inhibitory receptor. Therefore, processing of a heat shock protein, which can occur during the cellular stress that accompanies infection or inflammation, into a peptide that modifies an MHC class I molecule represents another mechanism for the immunosurveillance of stressed cells by NK cells. Both the innate and adaptive arms of the immune system are galvanized upon infection or transformation of healthy cells. Antigen-specific receptors of the adaptive immune system are selected to make the important distinction between normal structures and those that are either foreign or aberrant. In contrast, the innate immune system uses receptors that recognize structurally conserved molecular patterns on microorganisms, such as polysaccharides and CpG nucleotide sequences. NK cells are a subpopulation of lym-phocytes that bridge these two arms of the immune response. While they do not use V(D)J recombination to generate antigen-specific receptors, they nevertheless use a complex arsenal of receptors that either activate or inhibit their effector functions (cytotoxicity and/or cytokine release). There are multiple NK cell activation receptors on a given NK cell, which recognize ligands expressed on other cells, and an array of inhibitory receptors that monitor the integrity of MHC class I expression on other cells. Missing Self. The 'missing self' hypothesis was the first breakthrough in understanding specific recognition of target cells by NK cells, when it was appreciated that loss of MHC class I expression leads to sensitivity to lysis by NK cells (6). The hypothesis was validated by …