NK Cells Have Both Activation and Inhibition Receptors

Given that NK cells do not express antigen-specific receptors, the mechanism by which NK cells recognize altered self-cells and distinguish them from normal body cells baffled immu-nologists for years. The solution to the problem emerged with the realization that NK cells employ two different categories of receptors, one that delivers inhibition signals to NK cells, and another that delivers activation signals. Initially, it was thought that there were two receptors, one that activated and another that inhibited NK cells—the so-called two-receptor model. It is now clear that there are many different

FIGURE 14-13

Family of RAG-1 KO mice. These mice have no adaptive immunity because they lack T and B cells. However, NK cells and other mechanisms of innate immunity provide sufficient protection against infection that, if maintained in clean conditions, these mice can reproduce and raise healthy offspring. However, they are more susceptible to infection than normal mice and have reduced lifespans. [From the laboratory of R. A. Goldsby.]

FIGURE 14-13

Family of RAG-1 KO mice. These mice have no adaptive immunity because they lack T and B cells. However, NK cells and other mechanisms of innate immunity provide sufficient protection against infection that, if maintained in clean conditions, these mice can reproduce and raise healthy offspring. However, they are more susceptible to infection than normal mice and have reduced lifespans. [From the laboratory of R. A. Goldsby.]

cell-surface receptors for activation signals and a number of different kinds for inhibitory ones. Consequently, it is more appropriate to think in terms of an opposing-signals model rather than a two-receptor model. It is the balance between activating signals and inhibitory signals that is believed to enable NK cells to distinguish healthy cells from infected or cancerous ones. It is important to be aware that additional NK-activating signals can be delivered by soluble factors. These include cytokines such as a and p interferons, TNF-a, IL-12, and IL-15.

The exact nature of the membrane-bound receptors on NK cells that produce activation is not completely clear. Antibody crosslinking of many molecules found on the surface of NK cells can activate these cells artificially, but the natural ligands for many of these putative activation receptors (ARs) are not known. Some of the candidate ARs are members of a class of carbohydrate-binding proteins known as C-type lectins, so named because they have calcium-dependent carbohydrate-recognition domains. NKR-P1 is an example of a C-type lectin found on NK cells that has activation properties. In addition to lectins, other molecules on NK cells might be involved in activation, including CD2 (receptor for the adhesion molecule LFA-3), and the Fc7III receptor, CD16. Although CD16 is responsible for antibody-mediated recognition and killing of target cells by NK cells, it is probably not involved in non-antibody-dependent killing. In addition to the molecules already mentioned, three additional proteins, NKp30, NKp44, and NKp46, appear to play significant roles in the activation of human NK cells.

Clues to the sources of inhibitory signals came from studies of the killing of tumor cells and virus-infected cells by NK cells. It was noticed that the preferential killing of mouse tumor cells compared with normal cells correlated with a lack of expression of MHC molecules by the tumor cells. Experiments with human cells showed that NK cells lysed a B-cell line that was MHC deficient because it had been transformed by Epstein-Barr virus. However, when this cell line was transformed with human HLA genes so that it expressed high levels of MHC molecules, NK cells failed to lyse it. These observations led to the idea that NK cells target for killing cells that have aberrant MHC expression. Since many virus-infected and tumor cells have reduced MHC expression, this model made good physiological sense. Vindication of this proposal has come from the discovery of receptors on NK cells that produce inhibitory signals when they recognize MHC molecules on potential target cells. These inhibitory receptors on the NK cell then prevent NK-cell killing, proliferation, and cytokine release.

Two major groups of inhibitory receptors have been found on NK cells. One of these is a family of C-type-lectin-inhibitory receptors (CLIR), and the other is a group of Ig-superfamily-inhibitory receptors (ISIR) known as the killer-cell-inhibitory receptors (KIR). Even though these groups are chemically quite different, they are together referred to as the inhibitory-receptor superfamily (IRS). In humans, the

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