Natural Killer Cells and Recognition of MHC Class I Molecules: New Perspectives and Challenges in Immunology

INTRODUCTIONNatural killer (NK) cells were initially deﬁned by their ability tospontaneously lyze certain tumour cells and virally infected cells[1]. It was subsequently found that they also lyze certain normalcells, particularly hematopoietic blast cells displaying a mis-match at the MHC locus [2–5]. They do not, however, lyzenormal cells from the same host.The importance of NK cells, however, goes beyond theircapacity to lyze speciﬁc target cells. NK cells are also capableof producing cytokines [6], and the production of interferon-g(IFN-g) by NK cells plays an important role in regulating T cells,promoting a Th1 immune response. The alternative response, aTh2 response, is promoted in mice by a subset of T cells thatexpresses NK cell surface receptors, through the production ofinterleukin-4 [7].In the last decade, studies of the mechanisms by which NKcells are regulated has led to the discovery of families of NK cell-surface receptors that can either inhibit or activate NK cells. Theinhibitory receptors on NK cells belong to families of receptorsthat recognize class I MHC antigens, and it now appears that atleast some of the activating receptors may also do so. This has ledto new concepts about how the immune system distinguishes selffrom nonself and about the role of inhibitory receptors inregulating the immune response. The study of NK cells hasalso demonstrated the close relation and interaction between theadaptive or mnemonic immune system, represented by B cellsand T cells, and innate or nonadaptive immunity, which includesNK cells.This review begins with a brief survey of some of thebiological features of NK cells. It then discusses the concept ofinhibitory receptors, and the speciﬁc recognition of class I MHCantigens by inhibitory receptors on NK cells. The differences inMHC recognition between rodent and human NK cells arediscussed, with comments on possible reasons for the apparentdivergence between these systems. The different recognitionsystems appear to have conserved the same mechanisms fortransmembrane signalling, a matter of current intensive investi-gation. Activating receptors for class I and other antigens arethen presented, and the possible reasons for having an array ofboth activating and inhibitory receptors present on single NKcells are discussed.The interplay of inhibitory and activating receptors on NKcells provides an interesting biological model, and demonstratesthe dynamic quality of immune regulation. NK cells, unlike T-and B cells, do not rest, awaiting a unique challenge. NK cells aresentinels in the immune system, ever vigilant in scanning thecellular environment for an imbalance in the appropriateactivating and inhibitory signals.SOME BIOLOGICAL PROPERTIES OF NKCELLSNK cells are circulating, CD3-negative lymphocytes with spe-cialized immunological functions and a unique proﬁle of cell-surface markers. In humans CD56 serves as a tag to distinguishNK cells from other non-T lymphocytes, whereas in the mouseand rat, NKR-P1 molecules, being members of a superfamily oftype II molecules with lectin domains [8, 9], subserve the samefunction [10].NK cells are found in several lymphoid and nonlymphoidcompartments, such as the spleen, liver and lungs, but they arerelatively sparsely represented in the lymph nodes under normalconditions [11, 12]. Unlike most T and B cells, particularly thelong-lived memory cells, NK cells do not recirculate betweenblood and lymph [12]. Their life span is also more limited, with a