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2B4 acts as a non-major histocompatibility complex binding inhibitory receptor on mouse natural killer cells

Kyung-Mi Lee1, Megan E McNerney, Susan E Stepp

  • 1Department of Biochemistry, Korea University College of Medicine, Sungbuk-Gu, Anam-Dong, Seoul 136-705, Korea. kyunglee@korea.ac.kr

The Journal of Experimental Medicine
|May 5, 2004
PubMed

Insights

Natural killer (NK) cells typically target threats, but the 2B4 receptor surprisingly inhibits their function. This discovery reveals 2B4 as a novel negative regulator of NK cell activity against tumors and allografts.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • Natural killer (NK) cells are crucial for immune surveillance against tumors and pathogens.
  • The 2B4 receptor (CD244) is expressed on NK cells, and its ligand CD48 is found on hematopoietic cells.
  • Previously, 2B4 was considered an activating receptor based on in vitro studies.

Purpose of the Study:

  • To investigate the precise role of the 2B4 receptor in NK cell-mediated cytotoxicity and cytokine production.
  • To determine if 2B4 functions as an activating or inhibitory receptor in vivo and in vitro.
  • To elucidate the signaling pathway of 2B4, particularly its dependence on SH2D1A.

Main Methods:

  • Utilized antibody-blocking strategies and 2B4-deficient NK cells.
  • Assessed NK cell-mediated lysis of tumor and allogeneic targets.
  • Measured interferon-gamma production.
  • Employed a peritoneal tumor clearance assay in vivo.
  • Used retroviral transduction to restore 2B4 expression in deficient cells.

Main Results:

  • Contrary to expectations, 2B4 ligation inhibited NK cell lysis of CD48(+) targets and interferon-gamma production.
  • Mice lacking 2B4 showed enhanced clearance of CD48(+) tumor cells in vivo.
  • Restoring 2B4 expression in deficient NK cells reinstated the inhibitory function.
  • 2B4-mediated inhibition occurred independently of SH2D1A expression.

Conclusions:

  • The 2B4 receptor acts as a non-major histocompatibility complex binding negative regulator of NK cell function.
  • This finding challenges the established view of 2B4 as solely an activating receptor.
  • 2B4 plays a significant role in controlling NK cell responses against tumors and in allograft rejection.

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