Trends in Immunology
Volume 32, Issue 8, August 2011, Pages 364-372
Journal home page for Trends in Immunology

Review
Unifying concepts of MHC-dependent natural killer cell education

https://doi.org/10.1016/j.it.2011.06.001Get rights and content

Natural killer (NK) cells, like B and T lymphocytes, are potent effector cells that are crucial for immunity to tumors and infections. These effector responses must be controlled to avoid inadvertent attack against normal self. Yet, the mechanisms that guide NK cell tolerance differ from those guiding T and B cell tolerance. Here, we discuss how NK cells are licensed by self-MHC class I molecules through their inhibitory receptors which results in NK cell functional competence to be triggered through their activation receptors. We discuss recent data with respect to issues related to licensing, thereby providing a framework for unifying concepts on NK cell education.

Section snippets

Natural killer (NK) cell receptors: activation and inhibition

NK cells are endowed with potent effector mechanisms such as cytotoxicity and cytokine production. In contrast to other lymphocytes, NK cells do not express rearranged, antigen-specific receptors, and NK effector function is instead dictated by integration of signals received through germ-line-encoded receptors that can recognize ligands on their cellular targets [1]. Functionally, NK cell receptors are classified as activation or inhibitory [2] (Figure 1). Activation receptors, such as Ly49H

Licensing: MHC-dependent NK cell education

NK cells are regulated by the host MHC class I environment. In retrospect, this was first noted in the description of ‘hybrid resistance’, a phenomenon that defies predictions based on the classic laws of solid tissue transplantation (see Glossary) [10]. In hybrid resistance, F1 hybrid mice reject bone marrow (BM) grafts from either inbred parent but not from an F1 hybrid. Rejection is mediated by host NK cells, which are regulated by the host MHC class I environment 11, 12. Studies of β2

Mechanisms of licensing: ‘arming’ versus ‘disarming’?

Several mechanisms have been proposed to account for how NK cells become licensed through self-MHC-specific receptors. The best-known models are arming and disarming, proposed by Raulet and colleagues [30] (Figure 2, Figure 5). In the arming model, the self-specific inhibitory receptor provides all of the signals required for licensing to occur; more akin to a stimulatory receptor [31]. Although it might seem difficult to reconcile transmission of a positive signal through the ITIM, a domain

When does licensing occur…and with what?

There are two sites, termed site 1 and site 2, on MHC class I that potentially contact Ly49 receptors [45]. Site-directed mutagenesis indicates that site 2 is relevant for interaction in effector inhibition 46, 47. It is located below the peptide-binding domain and consists of contact residues in α1, α2, and α3 of the MHC class I heavy chain, and species-specific determinants present in mouse but not human β2m 46, 47, 48, 49. H2Dd mutant Tg mice indicate that site 2 is required for

Fine tuning of licensing?

We have discussed licensing as an all or none phenomenon, but this might be related to the original experimental systems that were designed to detect robustly the effect of various factors on education. Under the tuning or rheostat model, NK cells acquire function in a graded manner depending on receptor–self-MHC interactions [64]. NK cells with more inhibitory receptors that are capable of interacting with different self-MHC class I alleles are functionally more responsive to activation

Less is more?

Although data supporting the gain-in-function component of the tuning hypothesis are increasing, other data [70] seem to dispute the theory that more inhibitory interactions increase the potential for NK cell function. In the context of viral infection, NK cells expressing inhibitory receptors for self, that is, licensed NK cells, are less protective than unlicensed NK cells. Furthermore, licensed NK cells show less robust proliferation following infection. Additionally, injection of licensed

Loss of function: tuning down or anergy?

When NK cells from an MHC-sufficient mouse are transferred into an MHC-deficient host, they become hyporesponsive. These data suggest that licensing is reversible, and imply that a licensed NK cell in a WT mouse must continually sample the MHC class I environment to maintain its licensed or educated state [53]. In such a scenario, NK cell education is a dynamic process that occurs during the entire lifetime of the NK cell, rather than as a single event, such as with positive selection of T

Concluding remarks

Licensing, the education of NK cells by self-MHC, provides a unifying hypothesis that extends the missing-self hypothesis and also helps explain hybrid resistance. Recent data from a number of laboratories indicate that licensing effects vary in relation to the strength of the licensing signal. Moreover, MHC-dependent licensing effects on NK cell function can be bypassed depending on the context, such as viral infection.

Although much progress has been made in understanding the role of

Acknowledgments

The authors thank members of the Yokoyama laboratory who have contributed to understanding NK cell function and differentiation over the years. Work in the Yokoyama laboratory is supported by grants from the NIH (AI33903, AI51345, AI57160) and the Howard Hughes Medical Institute.

Glossary

Missing-self
Hypothesis to explain why NK cells are better able to attack cells lacking MHC class I molecules. NK cells survey tissues for normal levels of MHC class I molecules that are generally ubiquitously expressed. In the presence of normal target cell expression of MHC class I, NK cells do not attack, but NK cells can detect when MHC class I is downregulated, such as in viral infection. NK cells can then attack MHC-class-I-deficient cells.
Hybrid resistance
A phenomenon by which F1 hybrid

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