Trends in Immunology
ReviewUnifying concepts of MHC-dependent natural killer 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
References (74)
- et al.
In search of the ‘missing self’: MHC molecules and NK cell recognition
Immunol. Today
(1990) Tolerance of NK and LAK activity for HLA class I-deficient targets in a TAP1-deficient patient (bare lymphocyte syndrome type I)
Hum. Immunol.
(1999)Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors
Immunity
(1997)A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules
Blood
(2005)The NK cell receptor repertoire: formation, adaptation and exploitation
Curr. Opin. Immunol.
(2003)Human NK cell education by inhibitory receptors for MHC class I
Immunity
(2006)The requirement for NKG2D in NK cell-mediated rejection of parental bone marrow grafts is determined by MHC class I expressed by the graft recipient
Blood
(2010)- et al.
How do natural killer cells find self to achieve tolerance?
Immunity
(2006) - et al.
Inhibitory receptor signaling via tyrosine phosphorylation of the adapter CRK
Immunity
(2008) A “chimeric” C57L-derived Ly49 inhibitory receptor resembling the Ly49D activation receptor
Cell Immunol.
(2001)
Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244)
Blood
Education of human natural killer cells by activating killer cell immunoglobulin-like receptors
Blood
Binding of the natural killer cell inhibitory receptor Ly49A to its major histocompatibility complex class I ligand. Crucial contacts include both H-2Dd and beta 2-microglobulin
J. Biol. Chem.
A role for cis interaction between the inhibitory Ly49A receptor and MHC class I for natural killer cell education
Immunity
Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT
Blood
Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes
Blood
Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer
Blood
NK cell education: not an on-off switch but a tunable rheostat
Trends Immunol.
The strength of inhibitory input during education quantitatively tunes the functional responsiveness of individual natural killer cells
Blood
Identification of probabilistic transcriptional switches in the Ly49 gene cluster: a eukaryotic mechanism for selective gene activation
Immunity
Natural killer cells
NK cell recognition
Annu. Rev. Immunol.
A new self: MHC-class-I-independent natural-killer-cell self-tolerance
Nat. Rev. Immunol.
Cutting edge: identification of E-cadherin as a ligand for the murine killer cell lectin-like receptor G1
J. Immunol.
Killer cell lectin-like receptor G1 binds three members of the classical cadherin family to inhibit NK cell cytotoxicity
J. Exp. Med.
Negative signaling by inhibitory receptors: the NK cell paradigm
Immunol. Rev.
The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor
Nature
Roles of the NKG2D immunoreceptor and its ligands
Nat. Rev. Immunol.
Innate or adaptive immunity? The example of natural killer cells
Science
Hybrid resistance to parental marrow grafts: association with the K region of H-2
Science
Murine natural killer cells and marrow graft rejection
Annu. Rev. Immunol.
Prevention of allogeneic bone marrow graft rejection by H-2 transgene in donor mice
Science
Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice
Nature
Recognition of beta 2-microglobulin-negative (beta 2m-) T-cell blasts by natural killer cells from normal but not from beta 2m- mice: nonresponsiveness controlled by beta 2m- bone marrow in chimeric mice
Proc, Natl. Acad. Sci. U.S.A.
MHC class I deficiency: susceptibility to natural killer (NK) cells and impaired NK activity
Science
Licensing of natural killer cells by host major histocompatibility complex class I molecules
Nature
Development and function of CD94-deficient natural killer cells
PLoS ONE
Cited by (210)
Therapeutic potential of natural killer cells in neuroimmunological diseases
2024, Biomedicine and PharmacotherapyNatural killer cells for pancreatic cancer immunotherapy: Role of nanoparticles
2023, Cancer LettersMultifaceted nature of natural killer cells: Potential mode of interaction and shaping of stem cells
2022, NK Cells in Cancer Immunotherapy: Successes and ChallengesNatural Killer Cells in Cancer and Cancer Immunotherapy
2021, Cancer Letters