CEACAM1 on activated NK cells inhibits NKG2D-mediated cytolytic function and signaling

Shuhei Hosomi, Zhangguo Chen, Kristi Baker, Lanfen Chen, Yu Hwa Huang, Torsten Olszak, Sebastian Zeissig, Jing H. Wang, Ofer Mandelboim, Nicole Beauchemin, Lewis L. Lanier, Richard S. Blumberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageAmerican English
Pages (from-to)2473-2483
Number of pages11
JournalEuropean Journal of Immunology
Volume43
Issue number9
DOIs
StatePublished - Sep 2013

Keywords

  • CEACAM1
  • Cytolysis
  • Interleukin-2
  • NK cell
  • NKG2D

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