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

Shuhei Hosomi1, Zhangguo Chen, Kristi Baker

  • 1Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

European Journal of Immunology
|May 23, 2013
PubMed

Insights

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) on natural killer (NK) cells inhibits tumor cell killing by interacting with CEACAM1 on tumor cells. This blocks NKG2D signaling, impacting anti-tumor immunity.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is found on activated natural killer (NK) cells.
  • CEACAM1 expression inhibits the lysis of tumor cells that also express CEACAM1.
  • The precise mechanism behind this inhibition is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which CEACAM1 on NK cells inhibits tumor cell cytolysis.
  • To investigate the role of CEACAM1 in regulating NK cell-mediated cytotoxicity.
  • To understand the interaction between CEACAM1 and NKG2D signaling in NK cells.

Main Methods:

  • Studied interleukin-2-induced CEACAM1 expression on mouse and human NK cells.
  • Assessed the impact of CEACAM1 on NKG2D-stimulated cytolysis.
  • Investigated the requirement of CEACAM1 expression on both NK and tumor cells.
  • Analyzed the biochemical association between NKG2D and CEACAM1 upon co-engagement.
  • Examined the recruitment of Src homology phosphatase 1 and dephosphorylation of Vav1.

Main Results:

  • Interleukin-2-induced CEACAM1 on NK cells impairs NKG2D-mediated cytolysis of CEACAM1-bearing tumor cells.
  • This inhibitory effect requires CEACAM1 expression on both NK and tumor cells, suggesting trans-homophilic interactions.
  • Co-engagement of NKG2D and CEACAM1 leads to their biochemical association.
  • CEACAM1 recruits Src homology phosphatase 1, dephosphorylates Vav1, and blocks downstream signaling essential for cytolysis.

Conclusions:

  • CEACAM1 functions as an inhibitory receptor for NKG2D-mediated cytolysis on activated NK cells.
  • CEACAM1-mediated inhibition of NK cell cytotoxicity has significant implications for anti-tumor immunity.
  • Understanding this mechanism is crucial for developing strategies to overcome CEACAM1-induced immune evasion in cancer.
Keywords:
CEACAM1CytolysisInterleukin-2NK cellNKG2D

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