Differential Requirements for Vav Proteins in DAP10- and ITAM-mediated NK Cell Cytotoxicity

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2004 Sep 15

PMID 15365099

Citations 52

Authors

Marina Cella

Keiko Fujikawa

Ilaria Tassi

Sunjin Kim

Kevin Latinis

Shinzo Nishi

Wayne Yokoyama

Marco Colonna

Wojciech Swat

Affiliations

Soon will be listed here.

Abstract

Natural killer (NK) cells express multiple activating receptors that initiate signaling cascades through DAP10- or immunoreceptor tyrosine-based activation motif-containing adapters, including DAP12 and FcRgamma. Among downstream signaling mediators, the guanine nucleotide exchange factor Vav1 carries out a key role in activation. However, whether Vav1 regulates only some or all NK cell-activating pathways is matter of debate. It is also possible that two other Vav family molecules, Vav2 and Vav3, are involved in NK cell activation. Here, we examine the relative contribution of each of these exchange factors to NK cell-mediated cytotoxicity using mice lacking one, two, or all three Vav proteins. We found that Vav1 deficiency is sufficient to disrupt DAP10-mediated cytotoxicity, whereas lack of Vav2 and Vav3 profoundly impairs FcRgamma- and DAP12-mediated cytotoxicity. Our results provide evidence that these three Vav proteins function specifically in distinct pathways that trigger NK cell cytotoxicity.

Citing Articles

Harnessing B7-H6 for Anticancer Immunotherapy: Expression, Pathways, and Therapeutic Strategies.

Lee S, Kim J, Jang I, Jo S, Lee S, Oh S Int J Mol Sci. 2024; 25(19).

PMID: 39408655 PMC: 11476788. DOI: 10.3390/ijms251910326.

Advanced machine learning unveils CD8 + T cell genetic markers enhancing prognosis and immunotherapy efficacy in breast cancer.

Ma H, Shi L, Zheng J, Zeng L, Chen Y, Zhang S BMC Cancer. 2024; 24(1):1222.

PMID: 39354417 PMC: 11446097. DOI: 10.1186/s12885-024-12952-w.

Knockdowns of CD3zeta Chain in Primary NK Cells Illustrate Modulation of Antibody-Dependent Cellular Cytotoxicity Against Human Immunodeficiency Virus-1.

Sugawara S, Lee E, Craemer M, Pruitt A, Balachandran H, Gressens S AIDS Res Hum Retroviruses. 2024; 40(11):631-636.

PMID: 39041622 PMC: 11631794. DOI: 10.1089/AID.2023.0114.

Multiplex interrogation of the NK cell signalome reveals global downregulation of CD16 signaling during lentivirus infection through an IL-18/ADAM17-dependent mechanism.

Sugawara S, Hueber B, Woolley G, Terry K, Kroll K, Manickam C PLoS Pathog. 2023; 19(9):e1011629.

PMID: 37669308 PMC: 10503717. DOI: 10.1371/journal.ppat.1011629.

Actin Retrograde Flow Regulated by the Wiskott-Aldrich Syndrome Protein Drives the Natural Killer Cell Response.

Sabag B, Levy M, Kivelevitz J, Dashevsky N, Ben-Shmuel A, Puthenveetil A Cancers (Basel). 2022; 14(15).

PMID: 35954420 PMC: 9367451. DOI: 10.3390/cancers14153756.

References

Fujikawa K, Miletic A, Alt F, Faccio R, Brown T, Hoog J . Vav1/2/3-null mice define an essential role for Vav family proteins in lymphocyte development and activation but a differential requirement in MAPK signaling in T and B cells. J Exp Med. 2003; 198(10):1595-608. PMC: 2194126. DOI: 10.1084/jem.20030874. View

Raulet D . Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol. 2003; 3(10):781-90. DOI: 10.1038/nri1199. View

Zhang W, Sloan-Lancaster J, Kitchen J, Trible R, Samelson L . LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell. 1998; 92(1):83-92. DOI: 10.1016/s0092-8674(00)80901-0. View

Billadeau D, Brumbaugh K, Dick C, Schoon R, Bustelo X, Leibson P . The Vav-Rac1 pathway in cytotoxic lymphocytes regulates the generation of cell-mediated killing. J Exp Med. 1998; 188(3):549-59. PMC: 2212464. DOI: 10.1084/jem.188.3.549. View

Nakamura M, Linnemeyer P, Niemi E, Mason L, Ortaldo J, Ryan J . Mouse Ly-49D recognizes H-2Dd and activates natural killer cell cytotoxicity. J Exp Med. 1999; 189(3):493-500. PMC: 2192910. DOI: 10.1084/jem.189.3.493. View

Galandrini R, Palmieri G, Piccoli M, Frati L, Santoni A . Role for the Rac1 exchange factor Vav in the signaling pathways leading to NK cell cytotoxicity. J Immunol. 1999; 162(6):3148-52. View

Wu J, Song Y, Bakker A, Bauer S, Spies T, Lanier L . An activating immunoreceptor complex formed by NKG2D and DAP10. Science. 1999; 285(5428):730-2. DOI: 10.1126/science.285.5428.730. View

Mainiero F, Soriani A, Strippoli R, Jacobelli J, Gismondi A, Piccoli M . RAC1/P38 MAPK signaling pathway controls beta1 integrin-induced interleukin-8 production in human natural killer cells. Immunity. 2000; 12(1):7-16. DOI: 10.1016/s1074-7613(00)80154-5. View

Tomasello E, BLERY M, Vely F, Vivier E . Signaling pathways engaged by NK cell receptors: double concerto for activating receptors, inhibitory receptors and NK cells. Semin Immunol. 2000; 12(2):139-47. DOI: 10.1006/smim.2000.0216. View

10.

Billadeau D, Mackie S, Schoon R, Leibson P . The Rho family guanine nucleotide exchange factor Vav-2 regulates the development of cell-mediated cytotoxicity. J Exp Med. 2000; 192(3):381-92. PMC: 2193212. DOI: 10.1084/jem.192.3.381. View

11.

Doody G, Billadeau D, Clayton E, Hutchings A, Berland R, McAdam S . Vav-2 controls NFAT-dependent transcription in B- but not T-lymphocytes. EMBO J. 2000; 19(22):6173-84. PMC: 305817. DOI: 10.1093/emboj/19.22.6173. View

12.

Perussia B . Signaling for cytotoxicity. Nat Immunol. 2001; 1(5):372-4. DOI: 10.1038/80808. View

13.

Jiang K, Zhong B, Gilvary D, Corliss B, Hong-Geller E, Wei S . Pivotal role of phosphoinositide-3 kinase in regulation of cytotoxicity in natural killer cells. Nat Immunol. 2001; 1(5):419-25. DOI: 10.1038/80859. View

14.

Colucci F, Rosmaraki E, Bregenholt S, Samson S, Di Bartolo V, Turner M . Functional dichotomy in natural killer cell signaling: Vav1-dependent and -independent mechanisms. J Exp Med. 2001; 193(12):1413-24. PMC: 2193296. DOI: 10.1084/jem.193.12.1413. View

15.

Chan G, Hanke T, Fischer K . Vav-1 regulates NK T cell development and NK cell cytotoxicity. Eur J Immunol. 2001; 31(8):2403-10. DOI: 10.1002/1521-4141(200108)31:8<2403::aid-immu2403>3.0.co;2-o. View

16.

McVicar D, Burshtyn D . Intracellular signaling by the killer immunoglobulin-like receptors and Ly49. Sci STKE. 2001; 2001(75):re1. DOI: 10.1126/stke.2001.75.re1. View

17.

Cerwenka A, Lanier L . Natural killer cells, viruses and cancer. Nat Rev Immunol. 2002; 1(1):41-9. DOI: 10.1038/35095564. View

18.

Reynolds L, Smyth L, Norton T, Freshney N, Downward J, Kioussis D . Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma1 via phosphoinositide 3-kinase-dependent and -independent pathways. J Exp Med. 2002; 195(9):1103-14. PMC: 2193701. DOI: 10.1084/jem.20011663. View

19.

Arase H, Mocarski E, Campbell A, Hill A, Lanier L . Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science. 2002; 296(5571):1323-6. DOI: 10.1126/science.1070884. View

20.

Furukawa H, Iizuka K, Poursine-Laurent J, Shastri N, Yokoyama W . A ligand for the murine NK activation receptor Ly-49D: activation of tolerized NK cells from beta 2-microglobulin-deficient mice. J Immunol. 2002; 169(1):126-36. DOI: 10.4049/jimmunol.169.1.126. View