Figure 2. Inhibitory MHC class I receptors enable NK cells to respond to ‘missing self’ MHC class I.

Mature NK cells express inhibitory receptors that interact with MHC class I expressed by healthy cells (self MHC class I), generating signals that prevent the NK cells from responding to self. This is illustrated in the left panel for a human NK cell that expresses the inhibitory HLA-E specific receptor CD94:NKG2A and the activating receptor NKG2D, specific for MICA. Encoded by an MHC gene, the latter is structurally similar to the heavy chains of MHC class I (MIC is the acronym for MHC class I-like chain, and A refers to the first of several MIC genes and pseudogenes) but unlike them does not associate with β₂-microglobulin (β₂-m) [111]. The healthy cell expresses insufficient MICA to engage NKG2D and generate an activating signal, while expressing a normal amount of HLA-E that engages CD94:NKG2A and sustains NK cell inhibition. In this manner, inhibitory receptor recognition of normal self HLA class I prevents NK cells from attacking healthy cells of the body. Shown in the right panel is the situation for a cell that has become unhealthy through infection with a virus or malignant transformation. Such situations of cellular stress, induce increased cell-surface expression of MICA, while expression of HLA class I is often reduced. The former leads to engagement of NKG2D and the generation of activating signals, while the latter will reduce or eliminate engagement of CD94:NKG2A, thus attenuating inhibitory signaling. These two effects co-operate to activate the NK cell, which can then kill the unhealthy cells and secrete cytokines such as inteferon-γ that recruit and activate other immune system cells.