A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules

Fernandez, Nadine; Treiner, Emmanuel; Vance, Russell E.; Jamieson, Amanda M.; Lemieux, Suzanne; Raulet, David H.

doi:10.1182/blood-2004-08-3156

Cited by 488 publications

(608 citation statements)

References 65 publications

Supporting

Mentioning

575

Contrasting

Unclassified

Order By: Relevance

“…Current models for NK cell education and tolerance regard the inhibitory input (or the lack of it) as important, either during the development to achieve functional maturity [39,40] To improve visualization, error bars (SEM) are only shown for the extreme curves. n 5 8 mice per group.…”

Section: Discussionmentioning

confidence: 99%

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

et al. 2010

View full text Add to dashboard Cite

Missing-self-reactivity can be mimicked by blocking self-specific inhibitory receptors on NK cells, leading to increased rejection of syngeneic tumor cells. Using a mouse model, we investigated whether Ab-mediated blocking of inhibitory receptors, to a degree where NK cells rejected syngeneic tumor cells, would still allow self-tolerance toward normal syngeneic cells. Ly49C/I inhibitory receptors on C57BL/6 (H-2 b ) NK cells were blocked with F(ab') 2 fragments of the mAb 5E6. Inhibitory receptor blockade in vivo caused rejection of i.v. inoculated fluorescence-labeled syngeneic lymphoma line cells but not of syngeneic spleen cells, BM cells or lymphoblasts. The selective rejection of tumor cells was NK celldependent and specifically induced by Ly49C/I blockade. Moreover, selective tumor rejection was maintained after treatment with 5E6 F(ab') 2 for 9 wk, arguing against the induction of NK cell anergy or autoreactivity during this time. Combination therapy using 5E6 F(ab') 2 together with high dose IL-2 treatment further increased lymphoma cell rejection. In addition, combination therapy reduced growth of melanoma cell line tumors established by s.c. inoculation 3 days before start of treatment. Our results demonstrate that inhibitory receptor blockade does not result in attack on normal cells, despite potent reactivity against MHC class I-expressing tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

et al. 2010

View full text Add to dashboard Cite

show abstract

“…However, such NK cells are self-tolerant because they are hyporesponsive after engagement of activating receptors. Conversely, NK cells that express inhibitory receptors for self-MHC are functionally competent [3,4]. Thus, in humans, it has been shown that KIR2DL2/L3 1 , KIR2DL1 1 or KIR3DL1 1 CD56 dim NK cells derived from donors expressing the corresponding HLA class I ligands (group C1 alleles, group C2 alleles and HLA allotypes with the Bw4 epitope, respectively) are more responsive to CD16 cross-linking and stimulation with class I negative target cells than other NK-cell subsets [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…However, it is still unclear whether the hyporesponsive phenotype is stable or whether it can be reversed in certain contexts. Indeed, during infection with Listeria monocytogenes, NK cells that lack inhibitory receptors for self-MHC can produce as much IFN-g as competent NK cells [4]. Interestingly, NK cells derived from b2-microglobulin-deficient mice, which are hyporesponsive after certain activating stimuli, are still able to control cytomegalovirus infection in vivo [8].…”

Section: Introductionmentioning

confidence: 99%

“…Remarkably, we demonstrated for the first time that hyporesponsive NK cells that acquired KIR after cytokine stimulation became cytotoxic competent, suggesting that hyporesponsiveness is not a permanent feature but can be modulated under certain circumstances. Several in vivo data provided a hint that hyporesponsive NK cells that do not express inhibitory receptors can still function during infectious diseases [4,8]. Besides, it has been controversially discussed whether IL-2 stimulation could reverse NK-cell hyporesponsiveness [5,10].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Education of hyporesponsive NK cells by cytokines

et al. 2009

View full text Add to dashboard Cite

NK-cell tolerance to self is mediated via engagement of inhibitory receptors by cognate MHC molecules. This event is critical for NK-cell education to achieve functional competence. Thus, NK cells expressing self-MHC-specific inhibitory receptors are responsive to activating stimuli while those lacking such receptors are hyporesponsive. Nevertheless, the mechanisms underlying NK-cell education are still poorly understood. Here, we show that after stimulation with cytokines, hyporesponsive NK cells acquire stable expression of killer Ig-like receptors (KIR) as reflected by DNA hypomethylation of their KIR locus. Remarkably, only hyporesponsive NK cells that acquire KIR in the presence of their cognate MHC molecule gain functional competence and this process can occur in the absence of any accessory cells. Acquisition of competence does not result in autoreactivity, since acquired KIR are functional and therefore able to inhibit NK-cell cytotoxicity. Our data demonstrate that competent NK cells can be generated by cytokine stimulation, suggesting that NK-cell education might not only be an early event which takes place during NK-cell development but might also occur in the periphery during an immune response.Key words: Education . Killer Ig-like receptors . MHC . NK cells . Tolerance Supporting Information available onlineIntroduction NK cells are bone-marrow derived lymphocytes which play an important role in mediating innate immune responses to viruses, tumors and MHC-mismatched bone marrow grafts. The main effector functions of NK cells, such as cytokine production and cytotoxicity, are tightly regulated by a balance between activating and inhibitory signals. After engagement of multiple activating receptors expressed on their surface, NK cells can produce IFN-g and kill target cells. In most cases, ligands for activating receptors are pathogen-encoded molecules or self-proteins whose expression is up-regulated in transformed or infected cells. However, even normal cells can be lysed by NK cells if they fail to express a full set of self-MHC class I proteins [1]. These observations highlight NK-cell potential autoreactivity and raise the question of how NK cells discriminate diseased cells from healthy ones. NK cells are self-tolerant because they express inhibitory receptors specific for distinct polymorphic variants of MHC class I molecules which counteract the activating signals. Inhibitory receptors include the killer Ig-like receptors (KIR) in humans, the lectin-like Ly49 dimers in mice and the lectin-like CD94/NKG2A heterodimers in both species. Interestingly, the genes for inhibitory receptors and their cognate MHC class I ligands segregate independently, so genetic mechanisms cannot ensure that each NK-cell inhibitory receptor encounters its specific self-MHC class I molecule [2]. In line with this fact, some NK cells exist, which do not express any self-MHC class I-specific inhibitory receptor. However, 2548such NK cells are self-tolerant because they are hyporesponsive after engagement of activating ...

show abstract

“…Expression of one or more inhibitory Ly49 receptors is a key step by which the developing NK cells achieve full functional competency. 36,37 Our preliminary ex vivo analyses of fresh BM-derived NK cells revealed a significant reduction of Ly49A þ subset (44.0%) compared to WT. Similar reductions of Ly49A þ subset (41.1%) were seen in the spleenderived fresh NK cells (Figures 3a and b).…”

Section: Resultsmentioning

confidence: 93%

Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells

et al. 2008

View full text Add to dashboard Cite

Class IA phosphotidylinositol-3-kinases (PI3Ks) are a family of p85/p110 heterodimeric lipid kinases that are important in regulating signaling events in B and T cells. However, their role in natural killer (NK) cells is not understood. Here, using mice that lack the regulatory p85a subunit and its alternatively spliced variants p55a/p50a (collectively termed as p85a À/À ), we defined the role of PI3K in NK cell development and function. p85a À/À mice had impaired lineage commitment leading to reduced NK cellularity in the bone marrow and liver. p85a À/À NK cells showed a defective Ly49 subset specification and a decreased expression of CD43. Lack of p85a severely reduced the NK-mediated cytotoxicity against tumor cells representing 'induced-self' and 'missing-self'. More importantly, NKG2D and NK1.1 receptor-mediated cytokine and chemokine generation was significantly compromised in p85a À/À NK cells. These results reveal a previously unrecognized role of p85a in the development, terminal maturation, cytokine/chemokine generation and tumor clearance of NK cells.

show abstract

A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules

Cited by 488 publications

References 65 publications

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

Education of hyporesponsive NK cells by cytokines

Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells

Contact Info

Product

Resources

About