title: CEACAM1 on activated NK cells inhibits NKG2D-mediated cytolytic function and signaling.
abstract: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed on activated natural killer (NK) cells wherein it inhibits lysis of CEACAM1-bearing tumor cell lines. The mechanism for this is unknown. Here, we show that interleukin-2-induced expression of CEACAM1 on both mouse and primary human NK cells impairs the ability of NK gene complex group 2 member D (NKG2D) to stimulate cytolysis of CEACAM1-bearing cells. This process requires the expression of CEACAM1 on the NK cells and on the tumor cells, which is consistent with the involvement of trans-homophilic interactions between CEACAM1. Mechanistically, co-engagement of NKG2D and CEACAM1 results in a biochemical association between these two surface receptors and the recruitment of Src homology phosphatase 1 by CEACAM1 that leads to dephosphorylation of the guanine nucleotide exchange factor Vav1 and blockade of downstream signaling that is associated with the initiation of cytolysis. Thus, CEACAM1 on activated NK cells functions as an inhibitory receptor for NKG2D-mediated cytolysis, which has important implications for understanding the means by which CEACAM1 expression adversely affects tumor immunity.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Hosomi
authors.forename: Zhangguo
authors.initials: Z
authors.lastname: Chen
authors.forename: Kristi
authors.initials: K
authors.lastname: Baker
authors.forename: Lanfen
authors.initials: L
authors.lastname: Chen
authors.forename: Yu-Hwa
authors.initials: YH
authors.lastname: Huang
authors.forename: Torsten
authors.initials: T
authors.lastname: Olszak
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zeissig
authors.forename: Jing H
authors.initials: JH
authors.lastname: Wang
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
authors.forename: Nicole
authors.initials: N
authors.lastname: Beauchemin
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction
chemical_list: D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D007376:Interleukin-2; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D051567:Proto-Oncogene Proteins c-vav; D034741:RNA, Small Interfering; C496619:Vav1 protein, mouse; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse
keywords: CEACAM1; Cytolysis; Interleukin-2; NK cell; NKG2D