Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand–expressing tumor cells

Blood - Tập 106 Số 5 - Trang 1711-1717 - 2005
Jérôme D. Coudert1,2,3, Jacques Zimmer1,2,3, Elena Tomasello1,2,3, Marek Cebecauer1,2,3, Marco Colonna1,2,3, Éric Vivier1,2,3, Werner Held1,2,3
1From the Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Switzerland
2From the Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Switzerland; the Centre d'Immunologie INSERM/CNRS de Marseille-Luminy, France; and the Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO.
3the Centre d'Immunologie INSERM/CNRS de Marseille-Luminy, France

Tóm tắt

AbstractNKG2D is an activation receptor that allows natural killer (NK) cells to detect diseased host cells. The engagement of NKG2D with corresponding ligand results in surface modulation of the receptor and reduced function upon subsequent receptor engagement. However, it is not clear whether in addition to modulation the NKG2D receptor complex and/or its signaling capacity is preserved. We show here that the prolonged encounter with tumor cell-bound, but not soluble, ligand can completely uncouple the NKG2D receptor from the intracellular mobilization of calcium and the exertion of cell-mediated cytolysis. However, cytolytic effector function is intact since NKG2D ligand-exposed NK cells can be activated via the Ly49D receptor. While NKG2D-dependent cytotoxicity is impaired, prolonged ligand exposure results in constitutive interferon γ (IFNγ) production, suggesting sustained signaling. The functional changes are associated with a reduced presence of the relevant signal transducing adaptors DNAX-activating protein of 10 kDa (DAP-10) and killer cell activating receptor-associated protein/DNAX-activating protein of 12 kDa (KARAP/DAP-12). That is likely the consequence of constitutive NKG2D engagement and signaling, since NKG2D function and adaptor expression is restored to normal when the stimulating tumor cells are removed. Thus, the chronic exposure to tumor cells expressing NKG2D ligand alters NKG2D signaling and may facilitate the evasion of tumor cells from NK cell reactions. (Blood. 2005;106:1711-1717)

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Tài liệu tham khảo

Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nature Rev Immunol.2003;3: 781-790.

Diefenbach A, Jemsen ER, Jamieson AM, Raulet DH. Rae1 and H60 ligands of the NKG2D receptor stimulate tumor immunity. Nature.2001;413: 165-171.

Cerwenka A, Baron JL, Lanier LL. Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc Natl Acad Sci U S A.2001;98: 11521-11526.

Groh V, Wu J, Yee C, Spies T. Tumor-derived soluble MIC ligands impair expression of NKG2D and T cell activation. Nature.2002;419: 734-737.

Doubrovina ES, Doubrovin MM, Vider E, et al. Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma. J Immunol.2003;171: 6891-6899.

Ogasawara K, Hamerman JA, Hsin H, et al. Impairment of NK cell function by NKG2D modulation in NOD mice. Immunity.2003;18: 41-51.

Tomasello E, Desmoulins P-O, Chemin K, et al. Combined natural killer cell and dendritic cell functional deficiency in KARAP/DAP-12 loss-of-function mutant mice. Immunity.2000;13: 355-364.

Lowin-Kropf B, Kunz B, Schneider P, Held W. A role for the src family kinase Fyn in NK cell activation and the formation of the repertoire of Ly49 receptors. Eur J Immunol.2002;32: 773-782.

Doucey MA, Scarpellino L, Zimmer J, et al. Cis-association of Ly49A with MHC class I restricts natural killer cell inhibition. Nat Immunol.2004;5: 328-336.

Gilfillan S, Ho EL, Cella M, Yokoyama WM, Colonna M. NKG2D recruits two distinct adaptors to trigger NK cell activation and costimulation. Nat Immunol.2002;3: 1150-1155.

Diefenbach A, Tomasello E, Lucas M, et al. Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nat Immunol.2002;3: 1142-1149.

Diefenbach A, Jamieson AN, Liu S, Shastri N, Raulet DH. Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nat Immunol.2000;1: 95-97.

Berebi G, Takayama H, Sitkovsky MV. Antigen-receptor interaction requirement for conjugate formation and lethal-hit triggering by cytotoxic T lymphocytes can be bypassed by protein kinase C activators and calcium ionophores. Proc Natl Acad Sci U S A.1987;84: 1364-1368.

Zompi S, Hamermann JA, Ogasawara K, et al. NKG2D triggers cytototxicity in mouse NK cells lacking DAP-12 or Syk family kinases. Nat Immunol.2003;4: 565-572.

Abrams SI, Brahmi Z. The functional loss of human natural killer cell activity induced by K562 is reversible via an interleukin-2-dependent mechanism. Cell Immunol.1986;101: 558-570.

Jewett A, Bonavida B. Target-induced inactivation and cell death by apoptosis in a subset of human NK cells. J Immunol.1996;156: 907-915.

Sivori S, Falco M, Marcenaro E, et al. Early expression of triggering receptors and regulatory role of 2B4 in human natural killer cell precursors undergoing in vitro differentiation. Proc Natl Acad Sci U S A.2002;99: 4526-4531.

Carayannopoulos LN, Naidenko OV, Kinder J, Ho EL, Fremont DH, Yokoyama WM. Ligands for murine NKG2D display heterogenous binding behavior. Eur J Immunol.2002;32: 597-605.

André P, Castricioni R, Espéli M, et al. Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors. Eur J Immunol.2004;34: 961-971.

Rosen DB, Araki M, Hamerman JA, Chen T, Yamamura T, Lanier LL. A structural basis for the association of DAP12 with mouse, but not human NKG2D. J Immunol.2004;173: 2470-2478.

Kishimoto H, Kubo RT, Yorifuji H, Nakayama T, Asano Y, Tada T. Physical dissociation of the TCR-CD3 complex accompanies receptor ligation. J Exp Med.1995;182: 1997-2006.

Mizoguchi H, O'Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC. Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science.1992;258: 17951798.

Baniyash M. TCR ζ-chain downregulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol.2004;4: 675-687.

Hamermann JA, Ogasawara K, Lanier LL. Cutting edge: toll-like receptor signaling in macrophages induces ligands for the NKG2D receptor. J Immunol.2004;172: 2001-2005.

Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddel SR, Spies T. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol.2000;2: 255-260.

Sivori S, Pende D, Bottino C, et al. NKp46 is the major triggering receptor involved in the natural cytotoxicity of fresh or cultured human NK cells: correlation between surface density of NKp46 and natural cytotoxicity against autologous, allogeneic or xenogeneic target cells. Eur J Immunol.1999;29: 1656-1666.

Costello RT, Sivori S, Marcenaro E, et al. Defective expression and function of natural cell-triggering receptors in patients with acute myeloid leukemia. Blood.2002;99: 3661-3667.

De Maria A, Fogli M, Costa P, et al. The impaired NK cell cytolytic function in viremic HIV-1 infection is associated with reduced surface expression of natural cytotoxicity receptors (NKp46, NKp30 and NKp44). Eur J Immunol.2003;33: 2410-2418.

Castricioni R, Cantoni C, Della Chiesa M, et al. Transforming growth factor β1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci U S A.2003;100: 4120-4125.

Lee JC, Lee KM, Kim DW, Heo DS. Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol.2004;172: 7335-7340.

Diefenbach A, Hsia JK, Hsiung MY, Raulet DH. A novel ligand for the NKG2D receptor activates NK cells and macrophages and induces tumor immunity. Eur J Immunol.2003;33: 381-391.

Hayakawa Y, Kelly JM, Westwood JA, et al. Cutting edge: tumor rejection mediated by NKG2D receptor-ligand interaction is dependent upon perforin. J Immunol.2002;169: 5377-5381.

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Blood

Tập 106 Số 5

1711-1717

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