The Role of NKG2D and Its Ligands in Autoimmune Diseases: New Targets for Immunotherapy
Abstract
:1. Introduction
2. NKG2D and NKG2D-L
2.1. NKG2D Receptor
2.2. NKG2D-L
3. Role of NKG2D/NKG2D-L in Autoimmune Diseases
3.1. SLE
3.2. RA
3.3. Multiple Sclerosis (MS)
3.4. Type I Diabetes (T1DM)
3.5. Inflammatory Bowel Disease (IBD)
3.6. Celiac Disease (CeD)
4. NKG2D and NKG2D-L Are Key Targets in Autoimmune Diseases
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
NK | Natural killer |
NKG2D | Natural killer group 2 member D |
NKG2D-L | NKG2D ligand |
SLE | Systemic lupus erythematosus |
RA | Rheumatoid arthritis |
MS | Multiple sclerosis |
T1DM | Type I diabetes |
IBD | Inflammatory bowel disease |
CeD | Celiac disease |
TCR | T-cell receptor |
Klrk1 | Killer cell lectin-like receptor K subfamily member 1 gene |
KLRD1 | Killer cell lectin-like receptor D1 |
KLRC | Killer cell lectin-like receptor C |
DAP10 | DNAX-activating protein 10 |
DAP12 | DNAX-activating protein 12 |
YXXM | Tyr-XX-Meth |
PI3K | Phosphatidylinositol 3 kinase |
Grb2 | Growth factor receptor binding protein 2 |
ITAM | Immunoreceptor tyrosine-based activation motif |
ZAP70 | Zeta chain-related protein kinase 70 |
Syk | Splenic tyrosine kinase |
IL-15 | Interleukin-15 |
MIC | MHC class I chain-related protein |
ULBP | UL16-binding protein |
MICA | MHC class I chain-related protein A |
MICB | MHC class I chain-related protein B |
Mult-1 | Murine UL-16-binding protein-like transcript 1 |
MHC-I | Major histocompatibility complex class I |
TM | Transmembrane |
GPI | Glycosylphosphatidylinositol |
sMIC | Soluble MIC |
sNKG2DL | Soluble NKG2D-L |
CNS | Central nervous system |
sMICA | Soluble MICA |
sMICB | Soluble MICB |
IL-10 | Interleukin-10 |
IFN | Interferon |
TNF-α | Tumor necrosis factor-α |
SLEDAI | SLE Disease Activity Index |
SNP | Single nucleotide polymorphism |
FLS | Fibroblast-like synovial cells |
Tregs | Regulatory T cells |
AE | Antigen epitope |
C3G | Anthocyanin-3-O-glucoside |
Sirt6 | Sirtuin6 |
EULAR | European League Against Rheumatism |
CSF | Cerebrospinal fluid |
EAE | Experimental autoimmune encephalomyelitis |
sULBP4 | Soluble ULBP4 |
GM-CSF | Granulocyte-macrophage colony-stimulating factor |
IFN-γ | Interferon-γ |
RR-MS | Relapsing multiple sclerosis |
HbA1c | Hemoglobin A1c |
CD | Crohn’s disease |
UC | Ulcerative colitis |
IEC | Intestinal epithelial cells |
TL1A | Tumor necrosis factor (TNF)-like cytokine 1A |
DSS | Dextran sulfate sodium |
TGF-β | Transforming growth factor beta(β) |
Xbp1 | X-box binding protein 1 |
ER | Endoplasmic reticulum |
CDAI | Crohn’s Disease Activity Index |
LOT | Loss of oral tolerance |
IELs | Intraepithelial lymphocytes |
ACD | Active celiac disease |
TDCA | Taurodeoxycholic acid |
CTL | Cytotoxic T-lymphocyte |
Cyst-LTs | Cysteinyl leukotrienes |
HSP70 | Heat shock protein 70 |
SCID | Severe combined immunodeficiency |
References
- Zhang, Z.; Jin, L.; Liu, L.; Zhou, M.; Zhang, X.; Zhang, L. The intricate relationship between autoimmunity disease and neutrophils death patterns: A love-hate story. Apoptosis 2023, 28, 1259–1284. [Google Scholar] [CrossRef] [PubMed]
- Tan, G.; Spillane, K.M.; Maher, J. The Role and Regulation of the NKG2D/NKG2D Ligand System in Cancer. Biology 2023, 12, 1079. [Google Scholar] [CrossRef] [PubMed]
- Giorgetti, O.B.; O’Meara, C.P.; Schorpp, M.; Boehm, T. Origin and evolutionary malleability of T cell receptor α diversity. Nature 2023, 619, 193–200. [Google Scholar] [CrossRef] [PubMed]
- Zhang, H.; Yang, L.; Wang, T.; Li, Z. NK cell-based tumor immunotherapy. Bioact. Mater. 2024, 31, 63–86. [Google Scholar] [CrossRef] [PubMed]
- Kyrysyuk, O.; Wucherpfennig, K.W. Designing Cancer Immunotherapies That Engage T Cells and NK Cells. Annu. Rev. Immunol. 2023, 41, 17–38. [Google Scholar] [CrossRef] [PubMed]
- Babic, M.; Romagnani, C. [Role of innate receptors in chronic inflammation and autoimmunity]. Z. Rheumatol. 2022, 81, 628–634. [Google Scholar] [CrossRef] [PubMed]
- Alkhayer, R.; Ponath, V.; Frech, M.; Adhikary, T.; Graumann, J.; Neubauer, A.; von Strandmann, E.P. KLF4-mediated upregulation of the NKG2D ligand MICA in acute myeloid leukemia: A novel therapeutic target identified by enChIP. Cell Commun. Signal. 2023, 21, 94. [Google Scholar] [CrossRef]
- Thompson, A.A.; Harbut, M.B.; Kung, P.P.; Karpowich, N.K.; Branson, J.D.; Grant, J.C.; Hagan, D.; Pascual, H.A.; Bai, G.; Zavareh, R.B.; et al. Identification of small-molecule protein-protein interaction inhibitors for NKG2D. Proc. Natl. Acad. Sci. USA 2023, 120, e2216342120. [Google Scholar] [CrossRef]
- Frazao, A.; Rethacker, L.; Messaoudene, M.; Avril, M.F.; Toubert, A.; Dulphy, N.; Caignard, A. NKG2D/NKG2-Ligand Pathway Offers New Opportunities in Cancer Treatment. Front. Immunol. 2019, 10, 661. [Google Scholar] [CrossRef]
- Wang, J.; Li, C.D.; Sun, L. Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma. Biomolecules 2020, 10, 301. [Google Scholar] [CrossRef]
- Siemaszko, J.; Marzec-Przyszlak, A.; Bogunia-Kubik, K. NKG2D Natural Killer Cell Receptor-A Short Description and Potential Clinical Applications. Cells 2021, 10, 1420. [Google Scholar] [CrossRef] [PubMed]
- Jones, A.B.; Rocco, A.; Lamb, L.S.; Friedman, G.K.; Hjelmeland, A.B. Regulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression. Cancers 2022, 14, 2339. [Google Scholar] [CrossRef] [PubMed]
- Duan, S.; Guo, W.; Xu, Z.; He, Y.; Liang, C.; Mo, Y.; Wang, Y.; Xiong, F.; Guo, C.; Li, Y.; et al. Natural killer group 2D receptor and its ligands in cancer immune escape. Mol. Cancer 2019, 18, 29. [Google Scholar] [CrossRef] [PubMed]
- Stojanovic, A.; Correia, M.P.; Cerwenka, A. The NKG2D/NKG2DL Axis in the Crosstalk Between Lymphoid and Myeloid Cells in Health and Disease. Front. Immunol. 2018, 9, 827. [Google Scholar] [CrossRef] [PubMed]
- Billadeau, D.D.; Upshaw, J.L.; Schoon, R.A.; Dick, C.J.; Leibson, P.J. NKG2D-DAP10 triggers human NK cell–mediated killing via a Syk-independent regulatory pathway. Nat. Immunol. 2003, 4, 557–564. [Google Scholar] [CrossRef] [PubMed]
- Okkenhaug, K.; Vanhaesebroeck, B. PI3K in lymphocyte development, differentiation and activation. Nat. Rev. Immunol. 2003, 3, 317–330. [Google Scholar] [CrossRef] [PubMed]
- Park, S.-G.; Schulze-Luehrman, J.; Hayden, M.S.; Hashimoto, N.; Ogawa, W.; Kasuga, M.; Ghosh, S. The kinase PDK1 integrates T cell antigen receptor and CD28 coreceptor signaling to induce NF-κB and activate T cells. Nat. Immunol. 2009, 10, 158–166. [Google Scholar] [CrossRef]
- Lanier, L.L.; Corliss, B.C.; Wu, J.; Leong, C.; Phillips, J.H. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 1998, 391, 703–707. [Google Scholar] [CrossRef]
- Nabekura, T.; Gotthardt, D.; Niizuma, K.; Trsan, T.; Jenus, T.; Jonjic, S.; Lanier, L.L. Cutting Edge: NKG2D Signaling Enhances NK Cell Responses but Alone Is Insufficient to Drive Expansion during Mouse Cytomegalovirus Infection. J. Immunol. 2017, 199, 1567–1571. [Google Scholar] [CrossRef]
- Bauer, S.; Groh, V.; Wu, J.; Steinle, A.; Phillips, J.H.; Lanier, L.L.; Spies, T. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999, 285, 727–729. [Google Scholar] [CrossRef]
- Groh, V.; Rhinehart, R.; Randolph-Habecker, J.; Topp, M.S.; Riddell, S.R.; Spies, T. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat. Immunol. 2001, 2, 255–260. [Google Scholar] [CrossRef] [PubMed]
- Jamieson, A.M.; Diefenbach, A.; McMahon, C.W.; Xiong, N.; Carlyle, J.R.; Raulet, D.H. The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity 2002, 17, 19–29. [Google Scholar] [CrossRef] [PubMed]
- Wang, T.; Wei, L.; Meng, S.; Song, W.; Chen, Y.; Li, H.; Zhao, Q.; Jiang, Z.; Liu, D.; Ren, H.; et al. Coordinated Priming of NKG2D Pathway by IL-15 Enhanced Functional Properties of Cytotoxic CD4(+)CD28(−) T Cells Expanded in Systemic Lupus Erythematosus. Inflammation 2023, 46, 1587–1601. [Google Scholar] [CrossRef] [PubMed]
- Wu, Z.; Zhang, H.; Wu, M.; Peng, G.; He, Y.; Wan, N.; Zeng, Y. Targeting the NKG2D/NKG2D-L axis in acute myeloid leukemia. Biomed. Pharmacother. 2021, 137, 111299. [Google Scholar] [CrossRef] [PubMed]
- Lazarova, M.; Steinle, A. The NKG2D axis: An emerging target in cancer immunotherapy. Expert Opin. Ther. Targets 2019, 23, 281–294. [Google Scholar] [CrossRef] [PubMed]
- Raulet, D.H. Roles of the NKG2D immunoreceptor and its ligands. Nat. Rev. Immunol. 2003, 3, 781–790. [Google Scholar] [CrossRef] [PubMed]
- Tchacrome, I.; Zhu, Q.; Saleh, M.A.; Zou, Y. Diseases association with the polymorphic major histocompatibility complex class I related chain a: MICA gene. Transpl. Immunol. 2022, 75, 101665. [Google Scholar] [CrossRef]
- Carayannopoulos, L.N.; Naidenko, O.V.; Fremont, D.H.; Yokoyama, W.M. Cutting edge: Murine UL16-binding protein-like transcript 1: A newly described transcript encoding a high-affinity ligand for murine NKG2D. J. Immunol. 2002, 169, 4079–4083. [Google Scholar] [CrossRef]
- Li, P.; Morris, D.L.; Willcox, B.E.; Steinle, A.; Spies, T.; Strong, R.K. Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA. Nat. Immunol. 2001, 2, 443–451. [Google Scholar] [CrossRef]
- O’Callaghan, C.A.; Cerwenka, A.; Willcox, B.E.; Lanier, L.L.; Bjorkman, P.J. Molecular competition for NKG2D: H60 and RAE1 compete unequally for NKG2D with dominance of H60. Immunity 2001, 15, 201–211. [Google Scholar] [CrossRef]
- Carayannopoulos, L.N.; Naidenko, O.V.; Kinder, J.; Ho, E.L.; Fremont, D.H.; Yokoyama, W. Ligands for murine NKG2D display heterogeneous binding behavior. Eur. J. Immunol. 2002, 32, 597–605. [Google Scholar] [CrossRef] [PubMed]
- McFarland, B.J.; Kortemme, T.; Yu, S.F.; Baker, D.; Strong, R.K. Symmetry recognizing asymmetry: Analysis of the interactions between the C-type lectin-like immunoreceptor NKG2D and MHC class I-like ligands. Structure 2003, 11, 411–422. [Google Scholar] [CrossRef]
- Fan, J.; Shi, J.; Zhang, Y.; Liu, J.; An, C.; Zhu, H.; Wu, P.; Hu, W.; Qin, R.; Yao, D.; et al. NKG2D discriminates diverse ligands through selectively mechano-regulated ligand conformational changes. EMBO J. 2022, 41, e107739. [Google Scholar] [CrossRef] [PubMed]
- Lee, M.J.; Blish, C.A. Defining the role of natural killer cells in COVID-19. Nat. Immunol. 2023, 24, 1628–1638. [Google Scholar] [CrossRef] [PubMed]
- Mamessier, E.; Sylvain, A.; Thibult, M.L.; Houvenaeghel, G.; Jacquemier, J.; Castellano, R.; Gonçalves, A.; André, P.; Romagné, F.; Thibault, G.; et al. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J. Clin. Invest. 2011, 121, 3609–3622. [Google Scholar] [CrossRef] [PubMed]
- Watson, N.F.; Spendlove, I.; Madjd, Z.; McGilvray, R.; Green, A.R.; Ellis, I.O.; Scholefield, J.H.; Durrant, L.G. Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients. Int. J. Cancer 2006, 118, 1445–1452. [Google Scholar] [CrossRef]
- McGilvray, R.W.; Eagle, R.A.; Watson, N.F.; Al-Attar, A.; Ball, G.; Jafferji, I.; Trowsdale, J.; Durrant, L.G. NKG2D ligand expression in human colorectal cancer reveals associations with prognosis and evidence for immunoediting. Clin. Cancer Res. 2009, 15, 6993–7002. [Google Scholar] [CrossRef]
- Fuertes, M.B.; Domaica, C.I.; Zwirner, N.W. Leveraging NKG2D Ligands in Immuno-Oncology. Front. Immunol. 2021, 12, 713158. [Google Scholar] [CrossRef]
- Chitadze, G.; Kabelitz, D. Immune surveillance in glioblastoma: Role of the NKG2D system and novel cell-based therapeutic approaches. Scand. J. Immunol. 2022, 96, e13201. [Google Scholar] [CrossRef]
- Mele, D.; Pessino, G.; Trisolini, G.; Luchena, A.; Benazzo, M.; Morbini, P.; Mantovani, S.; Oliviero, B.; Mondelli, M.U.; Varchetta, S. Impaired intratumoral natural killer cell function in head and neck carcinoma. Front. Immunol. 2022, 13, 997806. [Google Scholar] [CrossRef]
- Shahrabi, S.; Zayeri, Z.D.; Ansari, N.; Hadad, E.H.; Rajaei, E. Flip-flops of natural killer cells in autoimmune diseases versus cancers: Immunologic axis. J. Cell Physiol. 2019, 234, 16998–17010. [Google Scholar] [CrossRef] [PubMed]
- Schepis, D.; Gunnarsson, I.; Eloranta, M.L.; Lampa, J.; Jacobson, S.H.; Kärre, K.; Berg, L. Increased proportion of CD56bright natural killer cells in active and inactive systemic lupus erythematosus. Immunology 2009, 126, 140–146. [Google Scholar] [CrossRef] [PubMed]
- Groh, V.; Bruhl, A.; El-Gabalawy, H.; Nelson, J.L.; Spies, T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 2003, 100, 9452–9457. [Google Scholar] [CrossRef] [PubMed]
- Lorenzo-Vizcaya, A.; Isenberg, D.A. Clinical trials in systemic lupus erythematosus: The dilemma-Why have phase III trials failed to confirm the promising results of phase II trials? Ann. Rheum. Dis. 2023, 82, 169–174. [Google Scholar] [CrossRef] [PubMed]
- Hervier, B.; Ribon, M.; Tarantino, N.; Mussard, J.; Breckler, M.; Vieillard, V.; Amoura, Z.; Steinle, A.; Klein, R.; Kötter, I.; et al. Increased Concentrations of Circulating Soluble MHC Class I-Related Chain A (sMICA) and sMICB and Modulation of Plasma Membrane MICA Expression: Potential Mechanisms and Correlation with Natural Killer Cell Activity in Systemic Lupus Erythematosus. Front. Immunol. 2021, 12, 633658. [Google Scholar] [CrossRef] [PubMed]
- Dai, Z.; Turtle, C.J.; Booth, G.C.; Riddell, S.R.; Gooley, T.A.; Stevens, A.M.; Spies, T.; Groh, V. Normally occurring NKG2D+CD4+ T cells are immunosuppressive and inversely correlated with disease activity in juvenile-onset lupus. J. Exp. Med. 2009, 206, 793–805. [Google Scholar] [CrossRef]
- Hamada, S.; Caballero-Benitez, A.; Duran, K.L.; Stevens, A.M.; Spies, T.; Groh, V. Soluble MICB in Plasma and Urine Explains Population Expansions of NKG2D(+)CD4 T Cells Inpatients with Juvenile-Onset Systemic Lupus Erythematosus. Open J. Immunol. 2017, 7, 1–17. [Google Scholar] [CrossRef]
- Yang, D.; Wang, H.; Ni, B.; He, Y.; Li, J.; Tang, Y.; Fu, X.; Wang, Q.; Xu, G.; Li, K.; et al. Mutual activation of CD4+ T cells and monocytes mediated by NKG2D-MIC interaction requires IFN-gamma production in systemic lupus erythematosus. Mol. Immunol. 2009, 46, 1432–1442. [Google Scholar] [CrossRef]
- Yang, D.; Tian, Z.; Zhang, M.; Yang, W.; Tang, J.; Wu, Y.; Ni, B. NKG2D(+)CD4(+) T Cells Kill Regulatory T Cells in a NKG2D-NKG2D Ligand- Dependent Manner in Systemic Lupus Erythematosus. Sci. Rep. 2017, 7, 1288. [Google Scholar] [CrossRef]
- Green, M.R.; Kennell, A.S.; Larche, M.J.; Seifert, M.H.; Isenberg, D.A.; Salaman, M.R. Natural killer cell activity in families of patients with systemic lupus erythematosus: Demonstration of a killing defect in patients. Clin. Exp. Immunol. 2005, 141, 165–173. [Google Scholar] [CrossRef]
- Puxeddu, I.; Bongiorni, F.; Chimenti, D.; Bombardieri, S.; Moretta, A.; Bottino, C.; Migliorini, P. Cell surface expression of activating receptors and co-receptors on peripheral blood NK cells in systemic autoimmune diseases. Scand. J. Rheumatol. 2012, 41, 298–304. [Google Scholar] [CrossRef] [PubMed]
- Van Belle, T.L.; von Herrath, M.G. The role of the activating receptor NKG2D in autoimmunity. Mol. Immunol. 2009, 47, 8–11. [Google Scholar] [CrossRef] [PubMed]
- Sourour, S.K.; Aboelenein, H.R.; Elemam, N.M.; Abdelhamid, A.K.; Salah, S.; Abdelaziz, A.I. Unraveling the expression of microRNA-27a* & NKG2D in peripheral blood mononuclear cells and natural killer cells of pediatric systemic lupus erythematosus patients. Int. J. Rheum. Dis. 2017, 20, 1237–1246. [Google Scholar] [CrossRef] [PubMed]
- Piotrowski, P.; Lianeri, M.; Olesińska, M.; Jagodziński, P.P. Prevalence of the NKG2D Thr72Ala polymorphism in patients with systemic lupus erythematosus. Mol. Biol. Rep. 2012, 39, 1343–1347. [Google Scholar] [CrossRef] [PubMed]
- Kabalak, G.; Thomas, R.M.; Martin, J.; Ortego-Centeno, N.; Jimenez-Alonso, J.; de Ramón, E.; Buyny, S.; Hamsen, S.; Gross, W.L.; Schnarr, S.; et al. Association of an NKG2D gene variant with systemic lupus erythematosus in two populations. Hum. Immunol. 2010, 71, 74–78. [Google Scholar] [CrossRef] [PubMed]
- Yoshida, K.; Komai, K.; Shiozawa, K.; Mashida, A.; Horiuchi, T.; Tanaka, Y.; Nose, M.; Hashiramoto, A.; Shiozawa, S. Role of the MICA polymorphism in systemic lupus erythematosus. Arthritis Rheum. 2011, 63, 3058–3066. [Google Scholar] [CrossRef] [PubMed]
- Yu, P.; Zhu, Q.; Chen, C.; Fu, X.; Li, Y.; Liu, L.; Luo, Q.; Wang, F.; Wang, Y. Association Between Major Histocompatibility Complex Class I Chain-Related Gene Polymorphisms and Susceptibility of Systemic Lupus Erythematosus. Am. J. Med. Sci. 2017, 354, 430–435. [Google Scholar] [CrossRef]
- Cui, D.; Xu, D.; Yue, S.; Yan, C.; Liu, W.; Fu, R.; Ma, W.; Tang, Y. Recent advances in the pharmacological applications and liver toxicity of triptolide. Chem. Biol. Interact. 2023, 382, 110651. [Google Scholar] [CrossRef]
- Fasth, A.E.; Björkström, N.K.; Anthoni, M.; Malmberg, K.J.; Malmström, V. Activating NK-cell receptors co-stimulate CD4(+)CD28(−) T cells in patients with rheumatoid arthritis. Eur. J. Immunol. 2010, 40, 378–387. [Google Scholar] [CrossRef]
- Goronzy, J.J.; Henel, G.; Sawai, H.; Singh, K.; Lee, E.B.; Pryshchep, S.; Weyand, C.M. Costimulatory pathways in rheumatoid synovitis and T-cell senescence. Ann. N. Y. Acad. Sci. 2005, 1062, 182–194. [Google Scholar] [CrossRef]
- Sáez-Borderías, A.; Gumá, M.; Angulo, A.; Bellosillo, B.; Pende, D.; López-Botet, M. Expression and function of NKG2D in CD4+ T cells specific for human cytomegalovirus. Eur. J. Immunol. 2006, 36, 3198–3206. [Google Scholar] [CrossRef] [PubMed]
- Schrambach, S.; Ardizzone, M.; Leymarie, V.; Sibilia, J.; Bahram, S. In vivo expression pattern of MICA and MICB and its relevance to auto-immunity and cancer. PLoS ONE 2007, 2, e518. [Google Scholar] [CrossRef] [PubMed]
- Steigerwald, J.; Raum, T.; Pflanz, S.; Cierpka, R.; Mangold, S.; Rau, D.; Hoffmann, P.; Kvesic, M.; Zube, C.; Linnerbauer, S.; et al. Human IgG1 antibodies antagonizing activating receptor NKG2D on natural killer cells. MAbs 2009, 1, 115–127. [Google Scholar] [CrossRef] [PubMed]
- Mariotte, A.; Bernardi, L.; Macquin, C.; DeCauwer, A.; Kotova, I.; Blüml, S.; Noël, D.; Scanu, A.; Punzi, L.; Carapito, R.; et al. NKG2D ligands in inflammatory joint diseases: Analysis in human samples and mouse models. Clin. Exp. Rheumatol. 2021, 39, 982–987. [Google Scholar] [CrossRef] [PubMed]
- Aramaki, T.; Ida, H.; Izumi, Y.; Fujikawa, K.; Huang, M.; Arima, K.; Tamai, M.; Kamachi, M.; Nakamura, H.; Kawakami, A.; et al. A significantly impaired natural killer cell activity due to a low activity on a per-cell basis in rheumatoid arthritis. Mod. Rheumatol. 2009, 19, 245–252. [Google Scholar] [CrossRef] [PubMed]
- Nielsen, N.; Pascal, V.; Fasth, A.E.; Sundström, Y.; Galsgaard, E.D.; Ahern, D.; Andersen, M.; Baslund, B.; Bartels, E.M.; Bliddal, H.; et al. Balance between activating NKG2D, DNAM-1, NKp44 and NKp46 and inhibitory CD94/NKG2A receptors determine natural killer degranulation towards rheumatoid arthritis synovial fibroblasts. Immunology 2014, 142, 581–593. [Google Scholar] [CrossRef] [PubMed]
- Wang, L.; Wang, Y.; Liu, C.; He, J.; He, X.; Zhang, X.; Zhu, C.; Sun, J.; Wang, Q.; Chen, H.; et al. Treg-targeted efficient-inducible platform for collagen-induced arthritis treatment. Mater. Today Bio 2023, 19, 100557. [Google Scholar] [CrossRef]
- Cammarata, I.; Martire, C.; Citro, A.; Raimondo, D.; Fruci, D.; Melaiu, O.; D’Oria, V.; Carone, C.; Peruzzi, G.; Cerboni, C.; et al. Counter-regulation of regulatory T cells by autoreactive CD8(+) T cells in rheumatoid arthritis. J. Autoimmun. 2019, 99, 81–97. [Google Scholar] [CrossRef]
- Wang, H.; Li, S.; Zhang, G.; Wu, H.; Chang, X. Potential therapeutic effects of cyanidin-3-O-glucoside on rheumatoid arthritis by relieving inhibition of CD38+ NK cells on Treg cell differentiation. Arthritis Res. Ther. 2019, 21, 220. [Google Scholar] [CrossRef]
- Wielińska, J.; Tarassi, K.; Iwaszko, M.; Kościńska, K.; Wysoczańska, B.; Mole, E.; Kitsiou, V.; Świerkot, J.; Kolossa, K.; Kouniaki, D.; et al. Shared epitope and polymorphism of MICA and NKG2D encoding genes in Greek and Polish patients with rheumatoid arthritis. Cent. Eur. J. Immunol. 2021, 46, 92–98. [Google Scholar] [CrossRef]
- Kirsten, H.; Petit-Teixeira, E.; Scholz, M.; Hasenclever, D.; Hantmann, H.; Heider, D.; Wagner, U.; Sack, U.; Hugo Teixeira, V.; Prum, B.; et al. Association of MICA with rheumatoid arthritis independent of known HLA-DRB1 risk alleles in a family-based and a case control study. Arthritis Res. Ther. 2009, 11, R60. [Google Scholar] [CrossRef] [PubMed]
- Mariaselvam, C.M.; Boukouaci, W.; Charron, D.; Krishnamoorthy, R.; Tamouza, R.; Misra, D.P.; Negi, V.S. Association of MICA-129 polymorphism and circulating soluble MICA level with rheumatoid arthritis in a south Indian Tamil population. Int. J. Rheum. Dis. 2018, 21, 656–663. [Google Scholar] [CrossRef] [PubMed]
- Mariaselvam, C.M.; Tamouza, R.; Krishnamoorthy, R.; Charron, D.; Misra, D.P.; Jain, V.K.; Negi, V.S. Association of NKG2D gene variants with susceptibility and severity of rheumatoid arthritis. Clin. Exp. Immunol. 2017, 187, 369–375. [Google Scholar] [CrossRef] [PubMed]
- Iwaszko, M.; Świerkot, J.; Kolossa, K.; Jeka, S.; Wiland, P.; Bogunia-Kubik, K. Influence of NKG2D Genetic Variants on Response to Anti-TNF Agents in Patients with Rheumatoid Arthritis. Genes 2018, 9, 64. [Google Scholar] [CrossRef] [PubMed]
- Carlini, F.; Lusi, V.; Rizzi, C.; Assogna, F.; Laroni, A. Cladribine Tablets Mode of Action, Learning from the Pandemic: A Narrative Review. Neurol. Ther. 2023, 12, 1477–1490. [Google Scholar] [CrossRef]
- Lassmann, H. Multiple Sclerosis Pathology. Cold Spring Harb. Perspect. Med. 2018, 8, a028936. [Google Scholar] [CrossRef] [PubMed]
- Broux, B.; Mizee, M.R.; Vanheusden, M.; van der Pol, S.; van Horssen, J.; Van Wijmeersch, B.; Somers, V.; de Vries, H.E.; Stinissen, P.; Hellings, N. IL-15 amplifies the pathogenic properties of CD4+CD28− T cells in multiple sclerosis. J. Immunol. 2015, 194, 2099–2109. [Google Scholar] [CrossRef]
- Ruck, T.; Bittner, S.; Gross, C.C.; Breuer, J.; Albrecht, S.; Korr, S.; Göbel, K.; Pankratz, S.; Henschel, C.M.; Schwab, N.; et al. CD4+NKG2D+ T cells exhibit enhanced migratory and encephalitogenic properties in neuroinflammation. PLoS ONE 2013, 8, e81455. [Google Scholar] [CrossRef]
- Saikali, P.; Antel, J.P.; Pittet, C.L.; Newcombe, J.; Arbour, N. Contribution of astrocyte-derived IL-15 to CD8 T cell effector functions in multiple sclerosis. J. Immunol. 2010, 185, 5693–5703. [Google Scholar] [CrossRef]
- Wisgalla, A.; Ramien, C.; Streitz, M.; Schlickeiser, S.; Lupu, A.R.; Diemert, A.; Tolosa, E.; Arck, P.C.; Bellmann-Strobl, J.; Siebert, N.; et al. Alterations of NK Cell Phenotype During Pregnancy in Multiple Sclerosis. Front. Immunol. 2022, 13, 907994. [Google Scholar] [CrossRef]
- Carmena Moratalla, A.; Carpentier Solorio, Y.; Lemaitre, F.; Farzam-Kia, N.; Levert, A.; Zandee, S.E.J.; Lahav, B.; Guimond, J.V.; Haddad, E.; Girard, M.; et al. Stress Signal ULBP4, an NKG2D Ligand, Is Upregulated in Multiple Sclerosis and Shapes CD8(+) T-Cell Behaviors. Neurol. Neuroimmunol. Neuroinflamm. 2022, 9, e1119. [Google Scholar] [CrossRef] [PubMed]
- Legroux, L.; Moratalla, A.C.; Laurent, C.; Deblois, G.; Verstraeten, S.L.; Arbour, N. NKG2D and Its Ligand MULT1 Contribute to Disease Progression in a Mouse Model of Multiple Sclerosis. Front. Immunol. 2019, 10, 154. [Google Scholar] [CrossRef] [PubMed]
- Carmena Moratalla, A.; Carpentier Solorio, Y.; Lemaître, F.; Farzam-Kia, N.; Da Cal, S.; Guimond, J.V.; Haddad, E.; Duquette, P.; Girard, J.M.; Prat, A.; et al. Specific alterations in NKG2D(+) T lymphocytes in relapsing-remitting and progressive multiple sclerosis patients. Mult. Scler. Relat. Disord. 2023, 71, 104542. [Google Scholar] [CrossRef] [PubMed]
- Tahrali, I.; Kucuksezer, U.C.; Akdeniz, N.; Altintas, A.; Uygunoglu, U.; Aktas-Cetin, E.; Deniz, G. CD3(−)CD56(+) NK cells display an inflammatory profile in RR-MS patients. Immunol. Lett. 2019, 216, 63–69. [Google Scholar] [CrossRef] [PubMed]
- Acar, N.P.; Tuncer, A.; Ozkazanc, D.; Ozbay, F.G.; Karaosmanoglu, B.; Goksen, S.; Sayat, G.; Taskiran, E.Z.; Esendagli, G.; Karabudak, R. An immunological and transcriptomics approach on differential modulation of NK cells in multiple sclerosis patients under interferon-β1 and fingolimod therapy. J. Neuroimmunol. 2020, 347, 577353. [Google Scholar] [CrossRef] [PubMed]
- Schwichtenberg, S.C.; Wisgalla, A.; Schroeder-Castagno, M.; Alvarez-González, C.; Schlickeiser, S.; Siebert, N.; Bellmann-Strobl, J.; Wernecke, K.D.; Paul, F.; Dörr, J.; et al. Fingolimod Therapy in Multiple Sclerosis Leads to the Enrichment of a Subpopulation of Aged NK Cells. Neurotherapeutics 2021, 18, 1783–1797. [Google Scholar] [CrossRef] [PubMed]
- Neumann, M.; Arnould, T.; Su, B.L. Encapsulation of stem-cell derived β-cells: A promising approach for the treatment for type 1 diabetes mellitus. J. Colloid. Interface Sci. 2023, 636, 90–102. [Google Scholar] [CrossRef]
- Blevins, K.S.; Jeong, J.H.; Ou, M.; Brumbach, J.H.; Kim, S.W. EphA2 targeting peptide tethered bioreducible poly(cystamine bisacrylamide-diamino hexane) for the delivery of therapeutic pCMV-RAE-1γ to pancreatic islets. J. Control. Release 2012, 158, 115–122. [Google Scholar] [CrossRef]
- Ogasawara, K.; Hamerman, J.A.; Ehrlich, L.R.; Bour-Jordan, H.; Santamaria, P.; Bluestone, J.A.; Lanier, L.L. NKG2D blockade prevents autoimmune diabetes in NOD mice. Immunity 2004, 20, 757–767. [Google Scholar] [CrossRef]
- Rodacki, M.; Svoren, B.; Butty, V.; Besse, W.; Laffel, L.; Benoist, C.; Mathis, D. Altered natural killer cells in type 1 diabetic patients. Diabetes 2007, 56, 177–185. [Google Scholar] [CrossRef]
- Kjellev, S.; Haase, C.; Lundsgaard, D.; Ursø, B.; Tornehave, D.; Markholst, H. Inhibition of NKG2D receptor function by antibody therapy attenuates transfer-induced colitis in SCID mice. Eur. J. Immunol. 2007, 37, 1397–1406. [Google Scholar] [CrossRef] [PubMed]
- Van Belle, T.L.; Ling, E.; Haase, C.; Bresson, D.; Ursø, B.; von Herrath, M.G. NKG2D blockade facilitates diabetes prevention by antigen-specific Tregs in a virus-induced model of diabetes. J. Autoimmun. 2013, 40, 66–73. [Google Scholar] [CrossRef] [PubMed]
- Guerra, N.; Pestal, K.; Juarez, T.; Beck, J.; Tkach, K.; Wang, L.; Raulet, D.H. A selective role of NKG2D in inflammatory and autoimmune diseases. Clin. Immunol. 2013, 149, 432–439. [Google Scholar] [CrossRef] [PubMed]
- Yoon Kim, D.; Kwon Lee, J. Type 1 and 2 diabetes are associated with reduced natural killer cell cytotoxicity. Cell Immunol. 2022, 379, 104578. [Google Scholar] [CrossRef] [PubMed]
- Larsen, J.; Dall, M.; Antvorskov, J.C.; Weile, C.; Engkilde, K.; Josefsen, K.; Buschard, K. Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion. Eur. J. Immunol. 2014, 44, 3056–3067. [Google Scholar] [CrossRef] [PubMed]
- Adlercreutz, E.H.; Weile, C.; Larsen, J.; Engkilde, K.; Agardh, D.; Buschard, K.; Antvorskov, J.C. A gluten-free diet lowers NKG2D and ligand expression in BALB/c and non-obese diabetic (NOD) mice. Clin. Exp. Immunol. 2014, 177, 391–403. [Google Scholar] [CrossRef] [PubMed]
- Harms, R.Z.; Yarde, D.N.; Guinn, Z.; Lorenzo-Arteaga, K.M.; Corley, K.P.; Cabrera, M.S.; Sarvetnick, N.E. Increased expression of IL-18 in the serum and islets of type 1 diabetics. Mol. Immunol. 2015, 64, 306–312. [Google Scholar] [CrossRef]
- Dean, J.W.; Peters, L.D.; Fuhrman, C.A.; Seay, H.R.; Posgai, A.L.; Stimpson, S.E.; Brusko, M.A.; Perry, D.J.; Yeh, W.I.; Newby, B.N.; et al. Innate inflammation drives NK cell activation to impair Treg activity. J. Autoimmun. 2020, 108, 102417. [Google Scholar] [CrossRef]
- Trembath, A.P.; Krausz, K.L.; Sharma, N.; Gerling, I.C.; Mathews, C.E.; Markiewicz, M.A. NKG2D Signaling within the Pancreatic Islets Reduces NOD Diabetes and Increases Protective Central Memory CD8(+) T-Cell Numbers. Diabetes 2020, 69, 1749–1762, Erratum in Diabetes 2021, 70, 2159. [Google Scholar] [CrossRef]
- Bretto, E.; Ribaldone, D.G.; Caviglia, G.P.; Saracco, G.M.; Bugianesi, E.; Frara, S. Inflammatory Bowel Disease: Emerging Therapies and Future Treatment Strategies. Biomedicines 2023, 11, 2249. [Google Scholar] [CrossRef]
- Heilmann, R.M.; Suchodolski, J.S. Is inflammatory bowel disease in dogs and cats associated with a Th1 or Th2 polarization? Vet. Immunol. Immunopathol. 2015, 168, 131–134. [Google Scholar] [CrossRef] [PubMed]
- Wang, F.; Peng, P.L.; Lin, X.; Chang, Y.; Liu, J.; Zhou, R.; Nie, J.Y.; Dong, W.G.; Zhao, Q.; Li, J. Regulatory role of NKG2D+ NK cells in intestinal lamina propria by secreting double-edged Th1 cytokines in ulcerative colitis. Oncotarget 2017, 8, 98945–98952. [Google Scholar] [CrossRef] [PubMed]
- Ge, L.Q.; Jiang, T.; Zhao, J.; Chen, Z.T.; Zhou, F.; Xia, B. Upregulated mRNA expression of major histocompatibility complex class I chain-related gene A in colon and activated natural killer cells of Chinese patients with ulcerative colitis. J. Dig. Dis. 2011, 12, 82–89. [Google Scholar] [CrossRef] [PubMed]
- Allez, M.; Tieng, V.; Nakazawa, A.; Treton, X.; Pacault, V.; Dulphy, N.; Caillat-Zucman, S.; Paul, P.; Gornet, J.M.; Douay, C.; et al. CD4+NKG2D+ T cells in Crohn’s disease mediate inflammatory and cytotoxic responses through MICA interactions. Gastroenterology 2007, 132, 2346–2358. [Google Scholar] [CrossRef] [PubMed]
- Muro, M.; López-Hernández, R.; Mrowiec, A. Immunogenetic biomarkers in inflammatory bowel diseases: Role of the IBD3 region. World J. Gastroenterol. 2014, 20, 15037–15048. [Google Scholar] [CrossRef] [PubMed]
- Espinoza, J.L.; Minami, M. Sensing Bacterial-Induced DNA Damaging Effects via Natural Killer Group 2 Member D Immune Receptor: From Dysbiosis to Autoimmunity and Carcinogenesis. Front. Immunol. 2018, 9, 52. [Google Scholar] [CrossRef] [PubMed]
- Vadstrup, K.; Bendtsen, F. Anti-NKG2D mAb: A New Treatment for Crohn’s Disease? Int. J. Mol. Sci. 2017, 18, 1997. [Google Scholar] [CrossRef]
- Camus, M.; Esses, S.; Pariente, B.; Le Bourhis, L.; Douay, C.; Chardiny, V.; Mocan, I.; Benlagha, K.; Clave, E.; Toubert, A.; et al. Oligoclonal expansions of mucosal T cells in Crohn’s disease predominate in NKG2D-expressing CD4 T cells. Mucosal. Immunol. 2014, 7, 325–334. [Google Scholar] [CrossRef]
- Pariente, B.; Mocan, I.; Camus, M.; Dutertre, C.A.; Ettersperger, J.; Cattan, P.; Gornet, J.M.; Dulphy, N.; Charron, D.; Lémann, M.; et al. Activation of the receptor NKG2D leads to production of Th17 cytokines in CD4+ T cells of patients with Crohn’s disease. Gastroenterology 2011, 141, 217–226.e2. [Google Scholar] [CrossRef]
- Hammoudi, N.; Hamoudi, S.; Bonnereau, J.; Bottois, H.; Pérez, K.; Bezault, M.; Hassid, D.; Chardiny, V.; Grand, C.; Gergaud, B.; et al. Autologous organoid co-culture model reveals T cell-driven epithelial cell death in Crohn’s Disease. Front. Immunol. 2022, 13, 1008456. [Google Scholar] [CrossRef]
- Tougaard, P.; Skov, S.; Pedersen, A.E.; Krych, L.; Nielsen, D.S.; Bahl, M.I.; Christensen, E.G.; Licht, T.R.; Poulsen, S.S.; Metzdorff, S.B.; et al. TL1A regulates TCRγδ+ intraepithelial lymphocytes and gut microbial composition. Eur. J. Immunol. 2015, 45, 865–875. [Google Scholar] [CrossRef] [PubMed]
- Qian, X.; Hu, C.; Han, S.; Lin, Z.; Xiao, W.; Ding, Y.; Zhang, Y.; Qian, L.; Jia, X.; Zhu, G.; et al. NK1.1(−) CD4(+) NKG2D(+) T cells suppress DSS-induced colitis in mice through production of TGF-β. J. Cell Mol. Med. 2017, 21, 1431–1444. [Google Scholar] [CrossRef] [PubMed]
- Hosomi, S.; Grootjans, J.; Tschurtschenthaler, M.; Krupka, N.; Matute, J.D.; Flak, M.B.; Martinez-Naves, E.; Gomez Del Moral, M.; Glickman, J.N.; Ohira, M.; et al. Intestinal epithelial cell endoplasmic reticulum stress promotes MULT1 up-regulation and NKG2D-mediated inflammation. J. Exp. Med. 2017, 214, 2985–2997. [Google Scholar] [CrossRef] [PubMed]
- Martín-Adrados, B.; Wculek, S.K.; Fernández-Bravo, S.; Torres-Ruiz, R.; Valle-Noguera, A.; Gomez-Sánchez, M.J.; Hernández-Walias, J.C.; Ferreira, F.M.; Corraliza, A.M.; Sancho, D.; et al. Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress. Front. Immunol. 2023, 14, 1185517. [Google Scholar] [CrossRef] [PubMed]
- Allez, M.; Sands, B.E.; Feagan, B.G.; D’Haens, G.; De Hertogh, G.; Randall, C.W.; Zou, B.; Johanns, J.; O’Brien, C.; Curran, M.; et al. A Phase 2b, Randomised, Double-blind, Placebo-controlled, Parallel-arm, Multicenter Study Evaluating the Safety and Efficacy of Tesnatilimab in Patients with Moderately to Severely Active Crohn’s Disease. J. Crohns. Colitis 2023, 17, 1235–1251. [Google Scholar] [CrossRef] [PubMed]
- Giuffrida, P.; Di Sabatino, A. Targeting T cells in inflammatory bowel disease. Pharmacol. Res. 2020, 159, 105040. [Google Scholar] [CrossRef] [PubMed]
- Komnick, M.R.; Esterházy, D. Protists protecting food tolerance. Trends Immunol. 2023, 44, 745–747. [Google Scholar] [CrossRef]
- Medina Sanchez, L.; Siller, M.; Zeng, Y.; Brigleb, P.H.; Sangani, K.A.; Soto, A.S.; Engl, C.; Laughlin, C.R.; Rana, M.; Van Der Kraak, L.; et al. The gut protist Tritrichomonas arnold restrains virus-mediated loss of oral tolerance by modulating dietary antigen-presenting dendritic cells. Immunity 2023, 56, 1862–1875.e9. [Google Scholar] [CrossRef]
- Sollid, L.M. Intraepithelial lymphocytes in celiac disease: License to kill revealed. Immunity 2004, 21, 303–304. [Google Scholar] [CrossRef]
- Rubio-Tapia, A.; Hill, I.D.; Semrad, C.; Kelly, C.P.; Greer, K.B.; Limketkai, B.N.; Lebwohl, B. American College of Gastroenterology Guidelines Update: Diagnosis and Management of Celiac Disease. Am. J. Gastroenterol. 2023, 118, 59–76. [Google Scholar] [CrossRef]
- Allegretti, Y.L.; Bondar, C.; Guzman, L.; Cueto Rua, E.; Chopita, N.; Fuertes, M.; Zwirner, N.W.; Chirdo, F.G. Broad MICA/B expression in the small bowel mucosa: A link between cellular stress and celiac disease. PLoS ONE 2013, 8, e73658. [Google Scholar] [CrossRef] [PubMed]
- Abadie, V.; Discepolo, V.; Jabri, B. Intraepithelial lymphocytes in celiac disease immunopathology. Semin. Immunopathol. 2012, 34, 551–566. [Google Scholar] [CrossRef] [PubMed]
- Hüe, S.; Mention, J.J.; Monteiro, R.C.; Zhang, S.; Cellier, C.; Schmitz, J.; Verkarre, V.; Fodil, N.; Bahram, S.; Cerf-Bensussan, N.; et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 2004, 21, 367–377. [Google Scholar] [CrossRef] [PubMed]
- Meresse, B.; Chen, Z.; Ciszewski, C.; Tretiakova, M.; Bhagat, G.; Krausz, T.N.; Raulet, D.H.; Lanier, L.L.; Groh, V.; Spies, T.; et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 2004, 21, 357–366. [Google Scholar] [CrossRef] [PubMed]
- Bhagat, G.; Naiyer, A.J.; Shah, J.G.; Harper, J.; Jabri, B.; Wang, T.C.; Green, P.H.; Manavalan, J.S. Small intestinal CD8+TCRgammadelta+NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease. J. Clin. Invest. 2008, 118, 281–293. [Google Scholar] [CrossRef] [PubMed]
- Girdhar, K.; Dogru, Y.D.; Huang, Q.; Yang, Y.; Tolstikov, V.; Raisingani, A.; Chrudinova, M.; Oh, J.; Kelley, K.; Ludvigsson, J.F.; et al. Dynamics of the gut microbiome, IgA response, and plasma metabolome in the development of pediatric celiac disease. Microbiome 2023, 11, 9. [Google Scholar] [CrossRef] [PubMed]
- Marafini, I.; Monteleone, I.; Di Fusco, D.; Sedda, S.; Cupi, M.L.; Fina, D.; Paoluzi, A.O.; Pallone, F.; Monteleone, G. Celiac Disease-Related Inflammation Is Marked by Reduction of Nkp44/Nkp46-Double Positive Natural Killer Cells. PLoS ONE 2016, 11, e0155103. [Google Scholar] [CrossRef]
- Tang, F.; Sally, B.; Lesko, K.; Discepolo, V.; Abadie, V.; Ciszewski, C.; Semrad, C.; Guandalini, S.; Kupfer, S.S.; Jabri, B. Cysteinyl leukotrienes mediate lymphokine killer activity induced by NKG2D and IL-15 in cytotoxic T cells during celiac disease. J. Exp. Med. 2015, 212, 1487–1495. [Google Scholar] [CrossRef]
- Roberts, A.I.; Lee, L.; Schwarz, E.; Groh, V.; Spies, T.; Ebert, E.C.; Jabri, B. NKG2D receptors induced by IL-15 costimulate CD28-negative effector CTL in the tissue microenvironment. J. Immunol. 2001, 167, 5527–5530. [Google Scholar] [CrossRef]
- Zhang, J.; Basher, F.; Wu, J.D. NKG2D Ligands in Tumor Immunity: Two Sides of a Coin. Front. Immunol. 2015, 6, 97. [Google Scholar] [CrossRef]
- Verneris, M.R.; Karimi, M.; Baker, J.; Jayaswal, A.; Negrin, R.S. Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood 2004, 103, 3065–3072. [Google Scholar] [CrossRef] [PubMed]
- Granzin, M.; Wagner, J.; Köhl, U.; Cerwenka, A.; Huppert, V.; Ullrich, E. Shaping of Natural Killer Cell Antitumor Activity by Ex Vivo Cultivation. Front. Immunol. 2017, 8, 458. [Google Scholar] [CrossRef] [PubMed]
- Park, Y.P.; Choi, S.C.; Kiesler, P.; Gil-Krzewska, A.; Borrego, F.; Weck, J.; Krzewski, K.; Coligan, J.E. Complex regulation of human NKG2D-DAP10 cell surface expression: Opposing roles of the γc cytokines and TGF-β1. Blood 2011, 118, 3019–3027. [Google Scholar] [CrossRef] [PubMed]
- Lazarova, M.; Steinle, A. Impairment of NKG2D-Mediated Tumor Immunity by TGF-β. Front. Immunol. 2019, 10, 2689. [Google Scholar] [CrossRef] [PubMed]
- Allez, M.; Skolnick, B.E.; Wisniewska-Jarosinska, M.; Petryka, R.; Overgaard, R.V. Anti-NKG2D monoclonal antibody (NNC0142-0002) in active Crohn’s disease: A randomised controlled trial. Gut 2017, 66, 1918–1925. [Google Scholar] [CrossRef]
- Ito, Y.; Kanai, T.; Totsuka, T.; Okamoto, R.; Tsuchiya, K.; Nemoto, Y.; Yoshioka, A.; Tomita, T.; Nagaishi, T.; Sakamoto, N.; et al. Blockade of NKG2D signaling prevents the development of murine CD4+ T cell-mediated colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2008, 294, G199–G207. [Google Scholar] [CrossRef]
- Ogasawara, K.; Benjamin, J.; Takaki, R.; Phillips, J.H.; Lanier, L.L. Function of NKG2D in natural killer cell-mediated rejection of mouse bone marrow grafts. Nat. Immunol. 2005, 6, 938–945. [Google Scholar] [CrossRef]
- Galazka, G.; Jurewicz, A.; Orlowski, W.; Stasiolek, M.; Brosnan, C.F.; Raine, C.S.; Selmaj, K. EAE tolerance induction with Hsp70-peptide complexes depends on H60 and NKG2D activity. J. Immunol. 2007, 179, 4503–4512. [Google Scholar] [CrossRef]
Title | Clinical Trial No. | Status | Actual Enrolment | Conditions | Phase | Year Last Updated |
---|---|---|---|---|---|---|
Predictive Factors of ANTI-TNF Response in Luminal Crohn’s Disease Complicated by Abscess | NCT02856763 | Completed | 125 participants | Crohn’s disease | / | 20 January 2021 |
Safety and Efficacy Study of JNJ-64304500 in Participants With Moderately to Severely Active Crohn’s Disease | NCT02877134 | Completed | 388 participants | Crohn’s disease | Phase 2 | 17 February 2023 |
A Study of JNJ-64304500 as Add-on Therapy in Participants With Active Crohn’s Disease | NCT04655807 | Withdrawn (sponsor decision) | / | Crohn’s disease | Phase 2 | 1 September 2021 |
Safety and Efficacy of NNC 0142-0000-0002 in Subjects With Moderately to Severely Active Crohn’s Disease | NCT01203631 | Completed | 78 participants | Inflammation Crohn’s disease | Phase 2 | 1 August 2016 |
Efficacy of NNC0142-0002 in Subjects With Rheumatoid Arthritis (RA) | NCT01181050 | Completed | 63 participants | Inflammation rheumatoid arthritis | Phase 2 | 3 October 2016 |
First-in-man Trial of NNC0142-0002 in Patients With Rheumatoid Arthritis | NCT00927927 | Completed | 65 participants | Inflammation rheumatoid arthritis | Phase 1 | 3 October 2016 |
Disease | Immune Cell Type | Observed NKG2D Ligands | Biological Effects of NKG2D-NKG2DL | Refs. |
---|---|---|---|---|
SLE | NKG2D+CD4+ T cell NK cell | MICA sMICB | secretion of IFN, TNF-α, and granzyme promotes expansion | [48,49] |
RA | NKG2D+CD4+ T cell NK cell | MICA sMICA | direct cytotoxicity decreased NKG2D expression | [43,64] |
MS | NKG2D+CD4+ T cell NKG2D+CD8+ T cell NK cell | sULBP4 | promotes migration promotion of CD8+T cell motility enhances production of pro-inflammatory cytokines GM-CSF and IFN-γ | [78,81] |
T1DM | NKG2D+CD8+ T cell NK cell | RAE-1 | direct cytotoxicity | [89,95,99] |
IBD | NKG2D+CD4+ T cell | MICA | secretion of IFN-γ | [104] |
CeD | NKG2D+IEL cell | MICA | direct cytotoxicity | [122] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Wei, L.; Xiang, Z.; Zou, Y. The Role of NKG2D and Its Ligands in Autoimmune Diseases: New Targets for Immunotherapy. Int. J. Mol. Sci. 2023, 24, 17545. https://doi.org/10.3390/ijms242417545
Wei L, Xiang Z, Zou Y. The Role of NKG2D and Its Ligands in Autoimmune Diseases: New Targets for Immunotherapy. International Journal of Molecular Sciences. 2023; 24(24):17545. https://doi.org/10.3390/ijms242417545
Chicago/Turabian StyleWei, Leiyan, Zhiqing Xiang, and Yizhou Zou. 2023. "The Role of NKG2D and Its Ligands in Autoimmune Diseases: New Targets for Immunotherapy" International Journal of Molecular Sciences 24, no. 24: 17545. https://doi.org/10.3390/ijms242417545
APA StyleWei, L., Xiang, Z., & Zou, Y. (2023). The Role of NKG2D and Its Ligands in Autoimmune Diseases: New Targets for Immunotherapy. International Journal of Molecular Sciences, 24(24), 17545. https://doi.org/10.3390/ijms242417545