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{{Infobox_gene}}
{{Infobox_gene}}
'''NKG2D''' is an activating receptor (transmembrane protein) belonging to the [[NKG2]] family of [[C-type lectin|C-type lectin-like receptors]].<ref name="pmid2007850">{{cite journal | vauthors = Houchins JP, Yabe T, McSherry C, Bach FH | title = DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells | journal = The Journal of Experimental Medicine | volume = 173 | issue = 4 | pages = 1017–20 | date = Apr 1991 | pmid = 2007850 | pmc = 2190798 | doi = 10.1084/jem.173.4.1017 }}</ref> NKG2D is encoded by ''KLRK1'' gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice<ref name="pmid 9177771">{{cite journal | vauthors = Brown MG, Fulmek S, Matsumoto K, Cho R, Lyons PA, Levy ER, Scalzo AA,Yokoyama MW| title = A 2-Mb YAC contig and physical map of the natural killer gene complex on mouse chromosome 6 | journal = Genomics | volume = 42 | issue = 1 | pages = 16–25 | date = 1997 | pmid = 9177771 | doi = 10.1006/geno.1997.4721 }}</ref> and chromosome 12 in humans.<ref name="pmid8436421">{{cite journal | vauthors = Yabe T, McSherry C, Bach FH, Fisch P, Schall RP, Sondel PM, Houchins JP| title = A multigene family on human chromosome 12 encodes natural killer-cell lectins | journal = Immunogenetics | volume = 37 | issue = 6| pages = 455–460 | date = 1993 | pmid = 8436421 | doi=10.1007/BF00222470 | s2cid = 27350036 }}</ref> In mice, it is expressed by [[Natural killer cell|NK cells]], [[Natural killer T cell|NK1.1<sup>+</sup> T cells]], [[Gamma delta T cell|γδ T cells]], activated [[Cytotoxic T cell|CD8<sup>+</sup> αβ T cells]] and activated [[macrophage]]s.<ref name="pmid 12150888 ">{{cite journal | vauthors = Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR, Raulet DH | title = The role of the NKG2D immunoreceptor in immune cell activation and natural killing | journal = Immunity | volume = 17 | issue = 1 | pages = 19–29 | date = 2002 | pmid = 12150888 | doi = 10.1016/S1074-7613(02)00333-3 }}</ref> In humans, it is expressed by [[Natural killer cell|NK cells]], [[Gamma delta T cell|γδ T cells]] and [[Cytotoxic T cell|CD8<sup>+</sup> αβ T cells]].<ref name="pmid10426993">{{cite journal | vauthors = Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T | title = Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA | journal = Science | volume = 285 | issue = 5428 | pages = 727–9 | date = Jul 1999 | pmid = 10426993 | doi = 10.1126/science.285.5428.727 }}</ref> NKG2D recognizes [[Induced-self antigen|induced-self proteins]] from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.<ref name="pmid14523385">{{cite journal | vauthors = Raulet DH | title = Roles of the NKG2D immunoreceptor and its ligands | journal = Nature Reviews. Immunology | volume = 3 | issue = 10 | pages = 781–90 | date = Oct 2003 | pmid = 14523385 | doi = 10.1038/nri1199 | s2cid = 18234848 }}</ref>
'''NKG2D''' is an activating receptor (transmembrane protein) belonging to the [[NKG2]] family of [[C-type lectin|C-type lectin-like receptors]].<ref name="pmid2007850">{{cite journal | vauthors = Houchins JP, Yabe T, McSherry C, Bach FH | title = DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells | journal = The Journal of Experimental Medicine | volume = 173 | issue = 4 | pages = 1017–20 | date = Apr 1991 | pmid = 2007850 | pmc = 2190798 | doi = 10.1084/jem.173.4.1017 }}</ref> NKG2D is encoded by ''KLRK1'' (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice<ref name="pmid 9177771">{{cite journal | vauthors = Brown MG, Fulmek S, Matsumoto K, Cho R, Lyons PA, Levy ER, Scalzo AA,Yokoyama MW| title = A 2-Mb YAC contig and physical map of the natural killer gene complex on mouse chromosome 6 | journal = Genomics | volume = 42 | issue = 1 | pages = 16–25 | date = 1997 | pmid = 9177771 | doi = 10.1006/geno.1997.4721 }}</ref> and chromosome 12 in humans.<ref name="pmid8436421">{{cite journal | vauthors = Yabe T, McSherry C, Bach FH, Fisch P, Schall RP, Sondel PM, Houchins JP| title = A multigene family on human chromosome 12 encodes natural killer-cell lectins | journal = Immunogenetics | volume = 37 | issue = 6| pages = 455–460 | date = 1993 | pmid = 8436421 | doi=10.1007/BF00222470 | s2cid = 27350036 }}</ref> In mice, it is expressed by [[Natural killer cell|NK cells]], [[Natural killer T cell|NK1.1<sup>+</sup> T cells]], [[Gamma delta T cell|γδ T cells]], activated [[Cytotoxic T cell|CD8<sup>+</sup> αβ T cells]] and activated [[macrophage]]s.<ref name="pmid 12150888 ">{{cite journal | vauthors = Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR, Raulet DH | title = The role of the NKG2D immunoreceptor in immune cell activation and natural killing | journal = Immunity | volume = 17 | issue = 1 | pages = 19–29 | date = 2002 | pmid = 12150888 | doi = 10.1016/S1074-7613(02)00333-3 }}</ref> In humans, it is expressed by [[Natural killer cell|NK cells]], [[Gamma delta T cell|γδ T cells]] and [[Cytotoxic T cell|CD8<sup>+</sup> αβ T cells]].<ref name="pmid10426993">{{cite journal | vauthors = Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T | title = Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA | journal = Science | volume = 285 | issue = 5428 | pages = 727–9 | date = Jul 1999 | pmid = 10426993 | doi = 10.1126/science.285.5428.727 }}</ref> NKG2D recognizes [[Induced-self antigen|induced-self proteins]] from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.<ref name="pmid14523385">{{cite journal | vauthors = Raulet DH | title = Roles of the NKG2D immunoreceptor and its ligands | journal = Nature Reviews. Immunology | volume = 3 | issue = 10 | pages = 781–90 | date = Oct 2003 | pmid = 14523385 | doi = 10.1038/nri1199 | s2cid = 18234848 }}</ref>


== Structure ==
== Structure ==
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=== RAET1/ULBP family ===
=== RAET1/ULBP family ===
Among ten known human ''RAET1/ULBP'' genes, six encode functional proteins: [[RAET1E|RAET1E/ULBP4]], [[RAET1G|RAET1G/ULBP5]], [[ULBP2|RAET1H/ULBP2]], [[ULBP1|RAET1/ULBP1]], [[RAET1L|RAET1L/ULBP6]], [[ULBP3|RAET1N/ULBP3]]. In mice, proteins from orthologous RAET1/ULBP family fall into three subfamilies: [[Rae-1 family|Rae-1]], [[H60 family|H60]], and [[Murine UL16 binding protein-like transcript|MULT-1]].<ref name="Carapito_2015" /> [[ULBP2]] is a stress-induced ligand often found on [[Cellular senescence|senescent cells]].<ref name="pmid32298812">{{cite journal | vauthors= Song P, Zhao Q, Zou M | title = Targeting senescent cells to attenuate cardiovascular disease progression | journal = [[Ageing Research Reviews]] | volume = 60 | pages=101072 | year = 2020 | doi = 10.1016/j.arr.2020.101072 | pmc=7263313 | pmid=32298812| pmc-embargo-date = July 1, 2021 }}</ref>
Among ten known human ''RAET1/ULBP'' genes, six encode functional proteins: [[RAET1E|RAET1E/ULBP4]], [[RAET1G|RAET1G/ULBP5]], [[ULBP2|RAET1H/ULBP2]], [[ULBP1|RAET1/ULBP1]], [[RAET1L|RAET1L/ULBP6]], [[ULBP3|RAET1N/ULBP3]]. In mice, proteins from orthologous RAET1/ULBP family fall into three subfamilies: [[Rae-1 family|Rae-1]], [[H60 family|H60]], and [[Murine UL16 binding protein-like transcript|MULT-1]].<ref name="Carapito_2015" /> [[ULBP2]] is a stress-induced ligand often found on [[Cellular senescence|senescent cells]].<ref name="pmid32298812">{{cite journal | vauthors= Song P, Zhao Q, Zou M | title = Targeting senescent cells to attenuate cardiovascular disease progression | journal = [[Ageing Research Reviews]] | volume = 60 | pages=101072 | year = 2020 | doi = 10.1016/j.arr.2020.101072 | pmc=7263313 | pmid=32298812| pmc-embargo-date = July 1, 2021 }}</ref>

=== NKG2D ligand regulation ===
NKG2D ligand expression is regulated on multiple levels such as transcriptional, RNA splicing, posttranscriptional and posttranslational. On transcriptional level, NKG2D ligands can be regulated by transcription factors or regulatory sequences in various molecular pathways. Also, regulation of NKG2D ligands after cell stress, proliferation signals, infection or oxidative stress is able to activate a DNA damage response. <ref>{{Cite journal|last=Cerboni|first=Cristina|last2=Fionda|first2=Cinzia|last3=Soriani|first3=Alessandra|last4=Zingoni|first4=Alessandra|last5=Doria|first5=Margherita|last6=Cippitelli|first6=Marco|last7=Santoni|first7=Angela|date=2014|title=The DNA Damage Response: A Common Pathway in the Regulation of NKG2D and DNAM-1 Ligand Expression in Normal, Infected, and Cancer Cells|url=http://journal.frontiersin.org/article/10.3389/fimmu.2013.00508/abstract|journal=Frontiers in Immunology|volume=4|doi=10.3389/fimmu.2013.00508|issn=1664-3224|pmc=PMC3882864|pmid=24432022}}</ref> Ligation of sensor kinases ATM and ATR leads to activation of different checkpoint kinases, such as Chk1 and Chk2, <ref>{{Cite journal|last=Sancar|first=Aziz|last2=Lindsey-Boltz|first2=Laura A.|last3=Ünsal-Kaçmaz|first3=Keziban|last4=Linn|first4=Stuart|date=2004-06|title=Molecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints|url=http://www.annualreviews.org/doi/10.1146/annurev.biochem.73.011303.073723|journal=Annual Review of Biochemistry|language=en|volume=73|issue=1|pages=39–85|doi=10.1146/annurev.biochem.73.011303.073723|issn=0066-4154}}</ref> which are important for the induction of ''MIC'', ''ULBP''s or ''Reat1'' genes <ref>{{Cite journal|last=Gasser|first=Stephan|last2=Orsulic|first2=Sandra|last3=Brown|first3=Eric J.|last4=Raulet|first4=David H.|date=2005-08|title=The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor|url=http://www.nature.com/articles/nature03884|journal=Nature|language=en|volume=436|issue=7054|pages=1186–1190|doi=10.1038/nature03884|issn=0028-0836|pmc=PMC1352168|pmid=15995699}}</ref> ) and p53 regulate ULBP-1 and 2.<ref>{{Cite journal|last=Textor|first=Sonja|last2=Fiegler|first2=Nathalie|last3=Arnold|first3=Annette|last4=Porgador|first4=Angel|last5=Hofmann|first5=Thomas G.|last6=Cerwenka|first6=Adelheid|date=2011-09-15|title=Human NK Cells Are Alerted to Induction of p53 in Cancer Cells by Upregulation of the NKG2D Ligands ULBP1 and ULBP2|url=http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-10-3211|journal=Cancer Research|language=en|volume=71|issue=18|pages=5998–6009|doi=10.1158/0008-5472.CAN-10-3211|issn=0008-5472}}</ref> One of the major signals for cell expression of NKG2D is the triggering of DDR along with the induction of senescence program. <ref>{{Cite journal|last=Gasser|first=Stephan|last2=Orsulic|first2=Sandra|last3=Brown|first3=Eric J.|last4=Raulet|first4=David H.|date=2005-08|title=The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor|url=http://www.nature.com/articles/nature03884|journal=Nature|language=en|volume=436|issue=7054|pages=1186–1190|doi=10.1038/nature03884|issn=0028-0836|pmc=PMC1352168|pmid=15995699}}</ref> RNA splicing is another mechanism influencing NKG2D ligand expression. For MICA,<ref>{{Cite journal|last=Gavlovsky|first=Pierre-Jean|last2=Tonnerre|first2=Pierre|last3=Gérard|first3=Nathalie|last4=Nedellec|first4=Steven|last5=Daman|first5=Andrew W.|last6=McFarland|first6=Benjamin J.|last7=Charreau|first7=Béatrice|date=2016-08-01|title=Alternative Splice Transcripts for MHC Class I–like MICA Encode Novel NKG2D Ligands with Agonist or Antagonist Functions|url=http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.1501416|journal=The Journal of Immunology|language=en|volume=197|issue=3|pages=736–746|doi=10.4049/jimmunol.1501416|issn=0022-1767}}</ref> ULBP4<ref>{{Cite journal|last=Cao|first=Wei|last2=Xi|first2=Xueyan|last3=Wang|first3=Zhun|last4=Dong|first4=Liling|last5=Hao|first5=Zhiyong|last6=Cui|first6=Lianxian|last7=Ma|first7=Chi|last8=He|first8=Wei|date=2008-08|title=Four novel ULBP splice variants are ligands for human NKG2D|url=https://academic.oup.com/intimm/article-lookup/doi/10.1093/intimm/dxn057|journal=International Immunology|language=en|volume=20|issue=8|pages=981–991|doi=10.1093/intimm/dxn057|issn=1460-2377}}</ref> and ULBP5, <ref>{{Cite journal|last=Eagle|first=Robert A.|last2=Flack|first2=Gillian|last3=Warford|first3=Anthony|last4=Martínez-Borra|first4=Jesús|last5=Jafferji|first5=Insiya|last6=Traherne|first6=James A.|last7=Ohashi|first7=Maki|last8=Boyle|first8=Louise H.|last9=Barrow|first9=Alexander D.|last10=Caillat-Zucman|first10=Sophie|last11=Young|first11=Neil T.|date=2009-02-18|title=Cellular Expression, Trafficking, and Function of Two Isoforms of Human ULBP5/RAET1G|url=https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0004503|journal=PLOS ONE|language=en|volume=4|issue=2|pages=e4503|doi=10.1371/journal.pone.0004503|issn=1932-6203|pmc=PMC2637608|pmid=19223974}}</ref> alternative splicing isoforms were proven, however, the molecular mechanisms of this type of regulation are unknown. In posttranscriptional regulation, stabilization of NKG2D ligand mRNA plays a key role, for example AUF1 protein which mediates RNA degradation.<ref>{{Cite journal|last=Vantourout|first=P.|last2=Willcox|first2=C.|last3=Turner|first3=A.|last4=Swanson|first4=C. M.|last5=Haque|first5=Y.|last6=Sobolev|first6=O.|last7=Grigoriadis|first7=A.|last8=Tutt|first8=A.|last9=Hayday|first9=A.|date=2014-04-09|title=Immunological Visibility: Posttranscriptional Regulation of Human NKG2D Ligands by the EGF Receptor Pathway|url=https://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.3007579|journal=Science Translational Medicine|language=en|volume=6|issue=231|pages=231ra49–231ra49|doi=10.1126/scitranslmed.3007579|issn=1946-6234}}</ref> Additionally, surface expression levels of NKG2D can be controlled by soluble forms of various protease-mediated cleavages and exosome expression. <ref>{{Cite journal|last=Zingoni|first=Alessandra|last2=Molfetta|first2=Rosa|last3=Fionda|first3=Cinzia|last4=Soriani|first4=Alessandra|last5=Paolini|first5=Rossella|last6=Cippitelli|first6=Marco|last7=Cerboni|first7=Cristina|last8=Santoni|first8=Angela|date=2018-03-12|title=NKG2D and Its Ligands: “One for All, All for One”|url=http://journal.frontiersin.org/article/10.3389/fimmu.2018.00476/full|journal=Frontiers in Immunology|volume=9|pages=476|doi=10.3389/fimmu.2018.00476|issn=1664-3224|pmc=PMC5890157|pmid=29662484}}</ref>


== Function ==
== Function ==
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Interventions to increase senescent cell surface ligands of the Natural Killer cell receptor NKG2D have been proposed as a [[senolytic]] therapy to remove senescent cells.<ref name="pmid31184599">{{cite journal | vauthors=Muñoz DP, Yannone SM, Daemen A, Sun Y, Vakar-Lopez F, Kawahara M, Freund AM, Rodier F, Wu JD, Desprez PY, Raulet DH, Nelson PS, van 't Veer LJ, Campisi J, Coppé JP | title=Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancer to aging | journal=[[JCI Insight]] | volume=5 | issue=14 | pages=124716 | year=2019 | doi = 10.1172/jci.insight.124716 | pmc=6675550 | pmid=31184599 }}</ref>
Interventions to increase senescent cell surface ligands of the Natural Killer cell receptor NKG2D have been proposed as a [[senolytic]] therapy to remove senescent cells.<ref name="pmid31184599">{{cite journal | vauthors=Muñoz DP, Yannone SM, Daemen A, Sun Y, Vakar-Lopez F, Kawahara M, Freund AM, Rodier F, Wu JD, Desprez PY, Raulet DH, Nelson PS, van 't Veer LJ, Campisi J, Coppé JP | title=Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancer to aging | journal=[[JCI Insight]] | volume=5 | issue=14 | pages=124716 | year=2019 | doi = 10.1172/jci.insight.124716 | pmc=6675550 | pmid=31184599 }}</ref>

== NKG2D and NK cells ==
NK cells - cytotoxic lymphocytes - are a key part of innate immunity, mainly in the early cytolytic defence against infections and tumours. In immune response, large number of receptors with activatory and inhibitory character are expressed on the surface of NK cells. Dominance of inhibitory signals manages retention of NK cells in the inactivated state under normal conditions.

One of the activating receptors is NKG2D receptor. A low expression of the receptor is observed already in the early NK cells precursor stages, also the concentration of receptors is increased with maturation of NK cells. <ref>{{Cite journal|last=Huntington|first=Nicholas D.|last2=Vosshenrich|first2=Christian A. J.|last3=Di Santo|first3=James P.|date=2007-09|title=Developmental pathways that generate natural-killer-cell diversity in mice and humans|url=http://www.nature.com/articles/nri2154|journal=Nature Reviews Immunology|language=en|volume=7|issue=9|pages=703–714|doi=10.1038/nri2154|issn=1474-1733}}</ref> In mice, an animal model for immunology, both NKG2D isoforms were detected.  During resting state, predominance of long forms of NKG2D is typical, while in activated cells there is a higher number of short forms. <ref>{{Cite journal|last=Rabinovich|first=Brian|last2=Li|first2=Jennifer|last3=Wolfson|first3=Martin|last4=Lawrence|first4=William|last5=Beers|first5=Courtney|last6=Chalupny|first6=Jan|last7=Hurren|first7=Rose|last8=Greenfield|first8=Brad|last9=Miller|first9=Richard|last10=Cosman|first10=David|date=2006-04|title=NKG2D splice variants: a reexamination of adaptor molecule associations|url=http://link.springer.com/10.1007/s00251-005-0078-x|journal=Immunogenetics|language=en|volume=58|issue=2-3|pages=81–88|doi=10.1007/s00251-005-0078-x|issn=0093-7711}}</ref>

Interaction with IL-15 receptor (IL-15R) is a crucial factor for development, homeostasis and survival of NK cells and NKG2D signalling seems to be similarly critical. <ref>{{Cite journal|last=Di Santo|first=James P.|date=2006-04|title=NATURAL KILLER CELL DEVELOPMENTAL PATHWAYS: A Question of Balance|url=http://dx.doi.org/10.1146/annurev.immunol.24.021605.090700|journal=Annual Review of Immunology|volume=24|issue=1|pages=257–286|doi=10.1146/annurev.immunol.24.021605.090700|issn=0732-0582}}</ref> Connection between these two pathways is the binding of DAP10, adaptor protein and signal transducer, which associates with IL-15R or NKG2D, respectively.<ref>{{Cite journal|last=Horng|first=Tiffany|last2=Bezbradica|first2=Jelena S|last3=Medzhitov|first3=Ruslan|date=2007-12|title=NKG2D signaling is coupled to the interleukin 15 receptor signaling pathway|url=http://www.nature.com/articles/ni1524|journal=Nature Immunology|language=en|volume=8|issue=12|pages=1345–1352|doi=10.1038/ni1524|issn=1529-2908}}</ref> This phenomenon was proven by experiments on mice knocked out in ''Klrk1'' – such mice have higher proliferation rate, faster differentiation and maturation of NK cells, resulting in a misbalance of immature NK cell subpopulations and higher susceptibility to apoptosis of NK cells. <ref>{{Cite journal|last=Gilfillan|first=Susan|last2=Ho|first2=Emily L.|last3=Cella|first3=Marina|last4=Yokoyama|first4=Wayne M.|last5=Colonna|first5=Marco|date=2002-12|title=NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation|url=http://www.nature.com/articles/ni857|journal=Nature Immunology|language=en|volume=3|issue=12|pages=1150–1155|doi=10.1038/ni857|issn=1529-2908}}</ref>

NKG2D is involved in the generation of peripheral tolerance by the effective downregulation of NKGD ligands, for the prevention from recognition by NK cells. It is supposed to act as a form of obstacle against NK cells' hyper-responsiveness to ligands, without complete education in bone marrow. <ref>{{Cite journal|last=Groh|first=V.|last2=Rhinehart|first2=R.|last3=Secrist|first3=H.|last4=Bauer|first4=S.|last5=Grabstein|first5=K. H.|last6=Spies|first6=T.|date=1999-06-08|title=Broad tumor-associated expression and recognition by tumor-derived T cells of MICA and MICB|url=http://www.pnas.org/cgi/doi/10.1073/pnas.96.12.6879|journal=Proceedings of the National Academy of Sciences|language=en|volume=96|issue=12|pages=6879–6884|doi=10.1073/pnas.96.12.6879|issn=0027-8424|pmc=PMC22010|pmid=10359807}}</ref> Tolerance of NK cells is likewise observed during pregnancy, when placenta produces soluble and exosome-bound ligands for NKGD2D and accumulates large number of NK cells which prevent recognition of fetus as non-self.<ref>{{Cite journal|last=Hedlund|first=Malin|last2=Stenqvist|first2=Ann-Christin|last3=Nagaeva|first3=Olga|last4=Kjellberg|first4=Lennart|last5=Wulff|first5=Marianne|last6=Baranov|first6=Vladimir|last7=Mincheva-Nilsson|first7=Lucia|date=2009-07-01|title=Human Placenta Expresses and Secretes NKG2D Ligands via Exosomes that Down-Modulate the Cognate Receptor Expression: Evidence for Immunosuppressive Function|url=http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.0803477|journal=The Journal of Immunology|language=en|volume=183|issue=1|pages=340–351|doi=10.4049/jimmunol.0803477|issn=0022-1767}}</ref>

== NKG2D and T cells ==
For priming of T cells, binding of ligand on T cell receptors (TCR), co-stimulation by membrane receptors and cytokines are all necessary components. Co-stimulation regulates responsiveness of T cells and NKG2D is one of well-documented co-stimulatory molecules for T cells.<ref>{{Cite journal|last=Groh|first=Veronika|last2=Rhinehart|first2=Rebecca|last3=Randolph-Habecker|first3=Julie|last4=Topp|first4=Max S.|last5=Riddell|first5=Stanley R.|last6=Spies|first6=Thomas|date=2001-03|title=Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells|url=http://www.nature.com/articles/ni0301_255|journal=Nature Immunology|language=en|volume=2|issue=3|pages=255–260|doi=10.1038/85321|issn=1529-2908}}</ref> , CD28 –mediated co-stimulation is required for promotion of cytokine production and cytotoxicity in CD8<sup>+</sup> T cells by NKG2D. <ref>{{Cite journal|last=Kavazović|first=Inga|last2=Lenartić|first2=Maja|last3=Jelenčić|first3=Vedrana|last4=Jurković|first4=Slaven|last5=Lemmermann|first5=Niels A.W.|last6=Jonjić|first6=Stipan|last7=Polić|first7=Bojan|last8=Wensveen|first8=Felix M.|date=2017-07|title=NKG2D stimulation of CD8 + T cells during priming promotes their capacity to produce cytokines in response to viral infection in mice|url=http://doi.wiley.com/10.1002/eji.201646805|journal=European Journal of Immunology|language=en|volume=47|issue=7|pages=1123–1135|doi=10.1002/eji.201646805}}</ref> For cytokine production and cytolytic killing by γδ T cells,  priming is not required, however NKG2D expression is constitutive while solely triggering NKG2D in γδ T cells does not mediate cytotoxicity.<ref>{{Cite journal|last=Nedellec|first=Steven|last2=Sabourin|first2=Caroline|last3=Bonneville|first3=Marc|last4=Scotet|first4=Emmanuel|date=2010-07-01|title=NKG2D Costimulates Human Vγ9Vδ2 T Cell Antitumor Cytotoxicity through Protein Kinase Cθ-Dependent Modulation of Early TCR-Induced Calcium and Transduction Signals|url=http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.1000373|journal=The Journal of Immunology|language=en|volume=185|issue=1|pages=55–63|doi=10.4049/jimmunol.1000373|issn=0022-1767}}</ref>

== NKG2D and B cells ==
In B cells, regulation of signalling threshold is affected by NKG2D, as proven in NKG2D deficient mice. These deficient mice have reduced number of B cells in spleen, <ref>{{Cite journal|last=Zafirova|first=Biljana|last2=Mandarić|first2=Sanja|last3=Antulov|first3=Ronald|last4=Krmpotić|first4=Astrid|last5=Jonsson|first5=Helena|last6=Yokoyama|first6=Wayne M.|last7=Jonjić|first7=Stipan|last8=Polić|first8=Bojan|date=2009-08|title=Altered NK Cell Development and Enhanced NK Cell-Mediated Resistance to Mouse Cytomegalovirus in NKG2D-Deficient Mice|url=https://linkinghub.elsevier.com/retrieve/pii/S107476130900315X|journal=Immunity|language=en|volume=31|issue=2|pages=270–282|doi=10.1016/j.immuni.2009.06.017|pmc=PMC2782462|pmid=19631564}}</ref> which is partially depended on DAP10. <ref>{{Cite journal|last=Wensveen|first=Felix M.|last2=Jelenčić|first2=Vedrana|last3=Polić|first3=Bojan|date=2018-03-08|title=NKG2D: A Master Regulator of Immune Cell Responsiveness|url=http://journal.frontiersin.org/article/10.3389/fimmu.2018.00441/full|journal=Frontiers in Immunology|volume=9|pages=441|doi=10.3389/fimmu.2018.00441|issn=1664-3224|pmc=PMC5852076|pmid=29568297}}</ref> In comparison to NK cells, mature B cells do not express NKG2D. <ref>{{Cite journal|last=Zafirova|first=Biljana|last2=Mandarić|first2=Sanja|last3=Antulov|first3=Ronald|last4=Krmpotić|first4=Astrid|last5=Jonsson|first5=Helena|last6=Yokoyama|first6=Wayne M.|last7=Jonjić|first7=Stipan|last8=Polić|first8=Bojan|date=2009-08|title=Altered NK Cell Development and Enhanced NK Cell-Mediated Resistance to Mouse Cytomegalovirus in NKG2D-Deficient Mice|url=https://linkinghub.elsevier.com/retrieve/pii/S107476130900315X|journal=Immunity|language=en|volume=31|issue=2|pages=270–282|doi=10.1016/j.immuni.2009.06.017|pmc=PMC2782462|pmid=19631564}}</ref>


==See also==
==See also==

Revision as of 14:28, 24 June 2021

KLRK1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesKLRK1, CD314, D12S2489E, KLR, NKG2-D, NKG2D, natural killer group 2D, killer cell lectin-like receptor K1, killer cell lectin like receptor K1
External IDsOMIM: 611817; MGI: 1196250; HomoloGene: 136440; GeneCards: KLRK1; OMA:KLRK1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

22914

27007

Ensembl

ENSG00000213809

ENSMUSG00000030149

UniProt

P26718

O54709

RefSeq (mRNA)

NM_007360

NM_001083322
NM_001286018
NM_033078

RefSeq (protein)

NP_001186734

NP_001076791
NP_001272947
NP_149069

Location (UCSC)Chr 12: 10.37 – 10.39 MbChr 6: 129.59 – 129.6 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors.[5] NKG2D is encoded by KLRK1 (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice[6] and chromosome 12 in humans.[7] In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages.[8] In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells.[9] NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.[10]

Structure

Human NKG2D receptor complex assembles into a hexameric structure. NKG2D itself forms a homodimer whose ectodomains serve for ligand binding.[11] Each NKG2D monomer is associated with DAP10 dimer. This association is maintained by ionic interaction of a positively charged arginine present in a transmembrane segment of NKG2D and negatively charged aspartic acids within both transmembrane regions of DAP10 dimer.[12] DAP10 functions as an adaptor protein and transduces the signal after the ligand binding by recruiting the p85 subunit of PI3K and Grb2-Vav1 complex which are responsible for subsequent downstream events.[13]

In mice, alternative splicing generates two distinct NKG2D isoforms: the long one (NKG2D-L) and the short one (NKG2D-S). NKG2D-L binds DAP10 similarly to human NKG2D. By contrast, NKG2D-S associates with two adaptor proteins: DAP10 and DAP12.[14] DAP10 recruits the p85 subunit of PI3K and a complex of Grb2 and Vav1.[13] DAP12 bears ITAM motif and activates protein tyrosine kinases Syk and Zap70 signalling.[15]

NKG2D ligands

NKG2D ligands are induced-self proteins which are completely absent or present only at low levels on surface of normal cells, but they are overexpressed by infected, transformed, senescent and stressed cells. Their expression is regulated at different stages (transcription, mRNA and protein stabilization, cleavage from the cell surface) by various stress pathways.[16] Among them, one of the most prominent stress pathways is DNA damage response. Genotoxic stress, stalled DNA replication, poorly regulated cell proliferation in tumorigenesis, viral replication or some viral products activate the ATM and ATR kinases. These kinases initiate the DNA damage response pathway which participates in NKG2D ligand upregulation. DNA damage response thus participate in alerting the immune system to the presence of potentially dangerous cells.[17]

All NKG2D ligands are homologous to MHC class I molecules and are divided into two families: MIC and RAET1/ULBP.

MIC family

Human MIC genes are located within the MHC locus and are composed of seven members (MICA-G), of which only MICA and MICB produce functional transcripts. In mice, MIC genes are absent.[18]

RAET1/ULBP family

Among ten known human RAET1/ULBP genes, six encode functional proteins: RAET1E/ULBP4, RAET1G/ULBP5, RAET1H/ULBP2, RAET1/ULBP1, RAET1L/ULBP6, RAET1N/ULBP3. In mice, proteins from orthologous RAET1/ULBP family fall into three subfamilies: Rae-1, H60, and MULT-1.[18] ULBP2 is a stress-induced ligand often found on senescent cells.[19]

NKG2D ligand regulation

NKG2D ligand expression is regulated on multiple levels such as transcriptional, RNA splicing, posttranscriptional and posttranslational. On transcriptional level, NKG2D ligands can be regulated by transcription factors or regulatory sequences in various molecular pathways. Also, regulation of NKG2D ligands after cell stress, proliferation signals, infection or oxidative stress is able to activate a DNA damage response. [20] Ligation of sensor kinases ATM and ATR leads to activation of different checkpoint kinases, such as Chk1 and Chk2, [21] which are important for the induction of MIC, ULBPs or Reat1 genes [22] ) and p53 regulate ULBP-1 and 2.[23] One of the major signals for cell expression of NKG2D is the triggering of DDR along with the induction of senescence program. [24] RNA splicing is another mechanism influencing NKG2D ligand expression. For MICA,[25] ULBP4[26] and ULBP5, [27] alternative splicing isoforms were proven, however, the molecular mechanisms of this type of regulation are unknown. In posttranscriptional regulation, stabilization of NKG2D ligand mRNA plays a key role, for example AUF1 protein which mediates RNA degradation.[28] Additionally, surface expression levels of NKG2D can be controlled by soluble forms of various protease-mediated cleavages and exosome expression. [29]

Function

NKG2D is a major recognition receptor for the detection and elimination of transformed and infected cells as its ligands are induced during cellular stress, either as a result of infection or genomic stress such as in cancer.[30] In NK cells, NKG2D serves as an activating receptor, which itself is able to trigger cytotoxicity. The function of NKG2D on CD8+ T cells is to send co-stimulatory signals to activate them.[31]

Role in viral infection

Viruses, as intracellular pathogens, can induce the expression of stress ligands for NKG2D. NKG2D is thought to be important in viral control as viruses have adapted mechanisms by which to evade NKG2D responses.[32] For example, cytomegalovirus (CMV) encodes a protein, UL16, which binds to NKG2D ligands ULBP1 and 2 (thus their name "UL16-binding protein") and MICB, which prevents their surface expression.[33]

Role in tumour control

As cancerous cells are "stressed", NKG2D ligands become upregulated, rendering the cell susceptible to NK cell-mediated lysis. Tumor cells that can evade NKG2D responses are thus more likely to propagate.[32][34]

Role in senescent cell removal

As part of the DNA damage response during induction of cellular senescence, cells upregulate the expression of NKG2D ligands that enable NK-mediated killing of senescent cells via the granule exocytosis pathway.[35][36] Specifically, MICA and ULBP2 proteins on senescent cells are recognized by the NKG2D receptor on Natural Killer cells, which is necessary for efficient recognition and elimination of senescent cells.[35]

Interventions to increase senescent cell surface ligands of the Natural Killer cell receptor NKG2D have been proposed as a senolytic therapy to remove senescent cells.[37]

NKG2D and NK cells

NK cells - cytotoxic lymphocytes - are a key part of innate immunity, mainly in the early cytolytic defence against infections and tumours. In immune response, large number of receptors with activatory and inhibitory character are expressed on the surface of NK cells. Dominance of inhibitory signals manages retention of NK cells in the inactivated state under normal conditions.

One of the activating receptors is NKG2D receptor. A low expression of the receptor is observed already in the early NK cells precursor stages, also the concentration of receptors is increased with maturation of NK cells. [38] In mice, an animal model for immunology, both NKG2D isoforms were detected.  During resting state, predominance of long forms of NKG2D is typical, while in activated cells there is a higher number of short forms. [39]

Interaction with IL-15 receptor (IL-15R) is a crucial factor for development, homeostasis and survival of NK cells and NKG2D signalling seems to be similarly critical. [40] Connection between these two pathways is the binding of DAP10, adaptor protein and signal transducer, which associates with IL-15R or NKG2D, respectively.[41] This phenomenon was proven by experiments on mice knocked out in Klrk1 – such mice have higher proliferation rate, faster differentiation and maturation of NK cells, resulting in a misbalance of immature NK cell subpopulations and higher susceptibility to apoptosis of NK cells. [42]

NKG2D is involved in the generation of peripheral tolerance by the effective downregulation of NKGD ligands, for the prevention from recognition by NK cells. It is supposed to act as a form of obstacle against NK cells' hyper-responsiveness to ligands, without complete education in bone marrow. [43] Tolerance of NK cells is likewise observed during pregnancy, when placenta produces soluble and exosome-bound ligands for NKGD2D and accumulates large number of NK cells which prevent recognition of fetus as non-self.[44]

NKG2D and T cells

For priming of T cells, binding of ligand on T cell receptors (TCR), co-stimulation by membrane receptors and cytokines are all necessary components. Co-stimulation regulates responsiveness of T cells and NKG2D is one of well-documented co-stimulatory molecules for T cells.[45] , CD28 –mediated co-stimulation is required for promotion of cytokine production and cytotoxicity in CD8+ T cells by NKG2D. [46] For cytokine production and cytolytic killing by γδ T cells,  priming is not required, however NKG2D expression is constitutive while solely triggering NKG2D in γδ T cells does not mediate cytotoxicity.[47]

NKG2D and B cells

In B cells, regulation of signalling threshold is affected by NKG2D, as proven in NKG2D deficient mice. These deficient mice have reduced number of B cells in spleen, [48] which is partially depended on DAP10. [49] In comparison to NK cells, mature B cells do not express NKG2D. [50]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000213809 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030149 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Houchins JP, Yabe T, McSherry C, Bach FH (Apr 1991). "DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells". The Journal of Experimental Medicine. 173 (4): 1017–20. doi:10.1084/jem.173.4.1017. PMC 2190798. PMID 2007850.
  6. ^ Brown MG, Fulmek S, Matsumoto K, Cho R, Lyons PA, Levy ER, Scalzo AA, Yokoyama MW (1997). "A 2-Mb YAC contig and physical map of the natural killer gene complex on mouse chromosome 6". Genomics. 42 (1): 16–25. doi:10.1006/geno.1997.4721. PMID 9177771.
  7. ^ Yabe T, McSherry C, Bach FH, Fisch P, Schall RP, Sondel PM, Houchins JP (1993). "A multigene family on human chromosome 12 encodes natural killer-cell lectins". Immunogenetics. 37 (6): 455–460. doi:10.1007/BF00222470. PMID 8436421. S2CID 27350036.
  8. ^ Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR, Raulet DH (2002). "The role of the NKG2D immunoreceptor in immune cell activation and natural killing". Immunity. 17 (1): 19–29. doi:10.1016/S1074-7613(02)00333-3. PMID 12150888.
  9. ^ Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T (Jul 1999). "Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA". Science. 285 (5428): 727–9. doi:10.1126/science.285.5428.727. PMID 10426993.
  10. ^ Raulet DH (Oct 2003). "Roles of the NKG2D immunoreceptor and its ligands". Nature Reviews. Immunology. 3 (10): 781–90. doi:10.1038/nri1199. PMID 14523385. S2CID 18234848.
  11. ^ Li P, Morris DL, Willcox BE, Steinle A, Spies T, Strong RK (May 2001). "Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA". Nature Immunology. 2 (5): 443–51. doi:10.1038/87757. PMID 11323699. S2CID 11096566.
  12. ^ Garrity D, Call ME, Feng J, Wucherpfennig KW (May 2005). "The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure". Proceedings of the National Academy of Sciences of the United States of America. 102 (21): 7641–6. Bibcode:2005PNAS..102.7641G. doi:10.1073/pnas.0502439102. PMC 1140444. PMID 15894612.
  13. ^ a b Upshaw JL, Arneson LN, Schoon RA, Dick CJ, Billadeau DD, Leibson PJ (May 2006). "NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells". Nature Immunology. 7 (5): 524–32. doi:10.1038/ni1325. PMID 16582911. S2CID 28236529.
  14. ^ Diefenbach A, Tomasello E, Lucas M, Jamieson AM, Hsia JK, Vivier E, Raulet DH (Dec 2002). "Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D". Nature Immunology. 3 (12): 1142–9. doi:10.1038/ni858. PMID 12426565. S2CID 14901451.
  15. ^ Gilfillan S, Ho EL, Cella M, Yokoyama WM, Colonna M (Dec 2002). "NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation". Nature Immunology. 3 (12): 1150–5. doi:10.1038/ni857. PMID 12426564. S2CID 5859797.
  16. ^ Raulet DH, Gasser S, Gowen BG, Deng W, Jung H (2013-01-01). "Regulation of ligands for the NKG2D activating receptor". Annual Review of Immunology. 31 (1): 413–41. doi:10.1146/annurev-immunol-032712-095951. PMC 4244079. PMID 23298206.
  17. ^ Gasser S, Orsulic S, Brown EJ, Raulet DH (Aug 2005). "The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor". Nature. 436 (7054): 1186–90. Bibcode:2005Natur.436.1186G. doi:10.1038/nature03884. PMC 1352168. PMID 15995699.
  18. ^ a b Carapito R, Bahram S (Sep 2015). "Genetics, genomics, and evolutionary biology of NKG2D ligands". Immunological Reviews. 267 (1): 88–116. doi:10.1111/imr.12328. PMID 26284473. S2CID 205213312.
  19. ^ Song P, Zhao Q, Zou M (2020). "Targeting senescent cells to attenuate cardiovascular disease progression". Ageing Research Reviews. 60: 101072. doi:10.1016/j.arr.2020.101072. PMC 7263313. PMID 32298812.{{cite journal}}: CS1 maint: PMC embargo expired (link)
  20. ^ Cerboni, Cristina; Fionda, Cinzia; Soriani, Alessandra; Zingoni, Alessandra; Doria, Margherita; Cippitelli, Marco; Santoni, Angela (2014). "The DNA Damage Response: A Common Pathway in the Regulation of NKG2D and DNAM-1 Ligand Expression in Normal, Infected, and Cancer Cells". Frontiers in Immunology. 4. doi:10.3389/fimmu.2013.00508. ISSN 1664-3224. PMC 3882864. PMID 24432022.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  21. ^ Sancar, Aziz; Lindsey-Boltz, Laura A.; Ünsal-Kaçmaz, Keziban; Linn, Stuart (2004-06). "Molecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints". Annual Review of Biochemistry. 73 (1): 39–85. doi:10.1146/annurev.biochem.73.011303.073723. ISSN 0066-4154. {{cite journal}}: Check date values in: |date= (help)
  22. ^ Gasser, Stephan; Orsulic, Sandra; Brown, Eric J.; Raulet, David H. (2005-08). "The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor". Nature. 436 (7054): 1186–1190. doi:10.1038/nature03884. ISSN 0028-0836. PMC 1352168. PMID 15995699. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  23. ^ Textor, Sonja; Fiegler, Nathalie; Arnold, Annette; Porgador, Angel; Hofmann, Thomas G.; Cerwenka, Adelheid (2011-09-15). "Human NK Cells Are Alerted to Induction of p53 in Cancer Cells by Upregulation of the NKG2D Ligands ULBP1 and ULBP2". Cancer Research. 71 (18): 5998–6009. doi:10.1158/0008-5472.CAN-10-3211. ISSN 0008-5472.
  24. ^ Gasser, Stephan; Orsulic, Sandra; Brown, Eric J.; Raulet, David H. (2005-08). "The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor". Nature. 436 (7054): 1186–1190. doi:10.1038/nature03884. ISSN 0028-0836. PMC 1352168. PMID 15995699. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  25. ^ Gavlovsky, Pierre-Jean; Tonnerre, Pierre; Gérard, Nathalie; Nedellec, Steven; Daman, Andrew W.; McFarland, Benjamin J.; Charreau, Béatrice (2016-08-01). "Alternative Splice Transcripts for MHC Class I–like MICA Encode Novel NKG2D Ligands with Agonist or Antagonist Functions". The Journal of Immunology. 197 (3): 736–746. doi:10.4049/jimmunol.1501416. ISSN 0022-1767.
  26. ^ Cao, Wei; Xi, Xueyan; Wang, Zhun; Dong, Liling; Hao, Zhiyong; Cui, Lianxian; Ma, Chi; He, Wei (2008-08). "Four novel ULBP splice variants are ligands for human NKG2D". International Immunology. 20 (8): 981–991. doi:10.1093/intimm/dxn057. ISSN 1460-2377. {{cite journal}}: Check date values in: |date= (help)
  27. ^ Eagle, Robert A.; Flack, Gillian; Warford, Anthony; Martínez-Borra, Jesús; Jafferji, Insiya; Traherne, James A.; Ohashi, Maki; Boyle, Louise H.; Barrow, Alexander D.; Caillat-Zucman, Sophie; Young, Neil T. (2009-02-18). "Cellular Expression, Trafficking, and Function of Two Isoforms of Human ULBP5/RAET1G". PLOS ONE. 4 (2): e4503. doi:10.1371/journal.pone.0004503. ISSN 1932-6203. PMC 2637608. PMID 19223974.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  28. ^ Vantourout, P.; Willcox, C.; Turner, A.; Swanson, C. M.; Haque, Y.; Sobolev, O.; Grigoriadis, A.; Tutt, A.; Hayday, A. (2014-04-09). "Immunological Visibility: Posttranscriptional Regulation of Human NKG2D Ligands by the EGF Receptor Pathway". Science Translational Medicine. 6 (231): 231ra49–231ra49. doi:10.1126/scitranslmed.3007579. ISSN 1946-6234.
  29. ^ Zingoni, Alessandra; Molfetta, Rosa; Fionda, Cinzia; Soriani, Alessandra; Paolini, Rossella; Cippitelli, Marco; Cerboni, Cristina; Santoni, Angela (2018-03-12). "NKG2D and Its Ligands: "One for All, All for One"". Frontiers in Immunology. 9: 476. doi:10.3389/fimmu.2018.00476. ISSN 1664-3224. PMC 5890157. PMID 29662484.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  30. ^ González S, López-Soto A, Suarez-Alvarez B, López-Vázquez A, López-Larrea C (Aug 2008). "NKG2D ligands: key targets of the immune response". Trends in Immunology. 29 (8): 397–403. doi:10.1016/j.it.2008.04.007. PMID 18602338.
  31. ^ Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR, Raulet DH (Jul 2002). "The role of the NKG2D immunoreceptor in immune cell activation and natural killing". Immunity. 17 (1): 19–29. doi:10.1016/S1074-7613(02)00333-3. PMID 12150888.
  32. ^ a b Zafirova B, Wensveen FM, Gulin M, Polić B (Nov 2011). "Regulation of immune cell function and differentiation by the NKG2D receptor". Cellular and Molecular Life Sciences. 68 (21): 3519–29. doi:10.1007/s00018-011-0797-0. PMC 3192283. PMID 21898152.
  33. ^ Welte SA, Sinzger C, Lutz SZ, Singh-Jasuja H, Sampaio KL, Eknigk U, Rammensee HG, Steinle A (Jan 2003). "Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein". European Journal of Immunology. 33 (1): 194–203. doi:10.1002/immu.200390022. PMID 12594848. S2CID 20718868.
  34. ^ Serrano AE, Menares-Castillo E, Garrido-Tapia M, Ribeiro CH, Hernández CJ, Mendoza-Naranjo A, Gatica-Andrades M, Valenzuela-Diaz R, Zúñiga R, López MN, Salazar-Onfray F, Aguillón JC, Molina MC (Mar 2011). "Interleukin 10 decreases MICA expression on melanoma cell surface". Immunology and Cell Biology. 89 (3): 447–57. doi:10.1038/icb.2010.100. hdl:10533/132162. PMID 20714339. S2CID 205150174.
  35. ^ a b Sagiv A, Burton DG, Moshayev Z, Vadai E, Wensveen F, Ben-Dor S, Golani O, Polic B, Krizhanovsky V (2016). "NKG2D ligands mediate immunosurveillance of senescent cells". Aging. 8 (2): 328–344. doi:10.18632/aging.100897. PMC 4789586. PMID 26878797.
  36. ^ Sagiv A, Biran A, Yon M, Simon J, Lowe SW, Krizhanovsky V. (2013). Granule exocytosis mediates immune surveillance of senescent cells Oncogene, 32, 1971–197, doi:10.1038/onc.2012.206
  37. ^ Muñoz DP, Yannone SM, Daemen A, Sun Y, Vakar-Lopez F, Kawahara M, Freund AM, Rodier F, Wu JD, Desprez PY, Raulet DH, Nelson PS, van 't Veer LJ, Campisi J, Coppé JP (2019). "Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancer to aging". JCI Insight. 5 (14): 124716. doi:10.1172/jci.insight.124716. PMC 6675550. PMID 31184599.
  38. ^ Huntington, Nicholas D.; Vosshenrich, Christian A. J.; Di Santo, James P. (2007-09). "Developmental pathways that generate natural-killer-cell diversity in mice and humans". Nature Reviews Immunology. 7 (9): 703–714. doi:10.1038/nri2154. ISSN 1474-1733. {{cite journal}}: Check date values in: |date= (help)
  39. ^ Rabinovich, Brian; Li, Jennifer; Wolfson, Martin; Lawrence, William; Beers, Courtney; Chalupny, Jan; Hurren, Rose; Greenfield, Brad; Miller, Richard; Cosman, David (2006-04). "NKG2D splice variants: a reexamination of adaptor molecule associations". Immunogenetics. 58 (2–3): 81–88. doi:10.1007/s00251-005-0078-x. ISSN 0093-7711. {{cite journal}}: Check date values in: |date= (help)
  40. ^ Di Santo, James P. (2006-04). "NATURAL KILLER CELL DEVELOPMENTAL PATHWAYS: A Question of Balance". Annual Review of Immunology. 24 (1): 257–286. doi:10.1146/annurev.immunol.24.021605.090700. ISSN 0732-0582. {{cite journal}}: Check date values in: |date= (help)
  41. ^ Horng, Tiffany; Bezbradica, Jelena S; Medzhitov, Ruslan (2007-12). "NKG2D signaling is coupled to the interleukin 15 receptor signaling pathway". Nature Immunology. 8 (12): 1345–1352. doi:10.1038/ni1524. ISSN 1529-2908. {{cite journal}}: Check date values in: |date= (help)
  42. ^ Gilfillan, Susan; Ho, Emily L.; Cella, Marina; Yokoyama, Wayne M.; Colonna, Marco (2002-12). "NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation". Nature Immunology. 3 (12): 1150–1155. doi:10.1038/ni857. ISSN 1529-2908. {{cite journal}}: Check date values in: |date= (help)
  43. ^ Groh, V.; Rhinehart, R.; Secrist, H.; Bauer, S.; Grabstein, K. H.; Spies, T. (1999-06-08). "Broad tumor-associated expression and recognition by tumor-derived T cells of MICA and MICB". Proceedings of the National Academy of Sciences. 96 (12): 6879–6884. doi:10.1073/pnas.96.12.6879. ISSN 0027-8424. PMC 22010. PMID 10359807.{{cite journal}}: CS1 maint: PMC format (link)
  44. ^ Hedlund, Malin; Stenqvist, Ann-Christin; Nagaeva, Olga; Kjellberg, Lennart; Wulff, Marianne; Baranov, Vladimir; Mincheva-Nilsson, Lucia (2009-07-01). "Human Placenta Expresses and Secretes NKG2D Ligands via Exosomes that Down-Modulate the Cognate Receptor Expression: Evidence for Immunosuppressive Function". The Journal of Immunology. 183 (1): 340–351. doi:10.4049/jimmunol.0803477. ISSN 0022-1767.
  45. ^ Groh, Veronika; Rhinehart, Rebecca; Randolph-Habecker, Julie; Topp, Max S.; Riddell, Stanley R.; Spies, Thomas (2001-03). "Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells". Nature Immunology. 2 (3): 255–260. doi:10.1038/85321. ISSN 1529-2908. {{cite journal}}: Check date values in: |date= (help)
  46. ^ Kavazović, Inga; Lenartić, Maja; Jelenčić, Vedrana; Jurković, Slaven; Lemmermann, Niels A.W.; Jonjić, Stipan; Polić, Bojan; Wensveen, Felix M. (2017-07). "NKG2D stimulation of CD8 + T cells during priming promotes their capacity to produce cytokines in response to viral infection in mice". European Journal of Immunology. 47 (7): 1123–1135. doi:10.1002/eji.201646805. {{cite journal}}: Check date values in: |date= (help)
  47. ^ Nedellec, Steven; Sabourin, Caroline; Bonneville, Marc; Scotet, Emmanuel (2010-07-01). "NKG2D Costimulates Human Vγ9Vδ2 T Cell Antitumor Cytotoxicity through Protein Kinase Cθ-Dependent Modulation of Early TCR-Induced Calcium and Transduction Signals". The Journal of Immunology. 185 (1): 55–63. doi:10.4049/jimmunol.1000373. ISSN 0022-1767.
  48. ^ Zafirova, Biljana; Mandarić, Sanja; Antulov, Ronald; Krmpotić, Astrid; Jonsson, Helena; Yokoyama, Wayne M.; Jonjić, Stipan; Polić, Bojan (2009-08). "Altered NK Cell Development and Enhanced NK Cell-Mediated Resistance to Mouse Cytomegalovirus in NKG2D-Deficient Mice". Immunity. 31 (2): 270–282. doi:10.1016/j.immuni.2009.06.017. PMC 2782462. PMID 19631564. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  49. ^ Wensveen, Felix M.; Jelenčić, Vedrana; Polić, Bojan (2018-03-08). "NKG2D: A Master Regulator of Immune Cell Responsiveness". Frontiers in Immunology. 9: 441. doi:10.3389/fimmu.2018.00441. ISSN 1664-3224. PMC 5852076. PMID 29568297.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  50. ^ Zafirova, Biljana; Mandarić, Sanja; Antulov, Ronald; Krmpotić, Astrid; Jonsson, Helena; Yokoyama, Wayne M.; Jonjić, Stipan; Polić, Bojan (2009-08). "Altered NK Cell Development and Enhanced NK Cell-Mediated Resistance to Mouse Cytomegalovirus in NKG2D-Deficient Mice". Immunity. 31 (2): 270–282. doi:10.1016/j.immuni.2009.06.017. PMC 2782462. PMID 19631564. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
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