Signaling through NK cell-associated CD137 promotes both helper function for CD8+ cytolytic T cells and responsiveness to IL-2 but not cytolytic activity

J Immunol. 2002 Oct 15;169(8):4230-6. doi: 10.4049/jimmunol.169.8.4230.

Abstract

NK cells possess both effector and regulatory activities that may be important during the antitumor immune response. In fact, the generation of antitumor immunity by the administration of an agonistic mAb against CD137 is NK cell-dependent. In this study, we report that NK cells could be induced by IL-2 and IL-15 to express CD137 and ligation of CD137-stimulated NK cell proliferation and IFN-gamma secretion, but not their cytolytic activity. Importantly, CD137-stimulated NK cells promoted the expansion of activated T cells in vitro, demonstrating immunoregulatory or "helper" activity for CD8(+)CTL. Furthermore, tumor-specific CTL activity against P815 tumor Ags was abrogated following anti-CD137 treatment in NK-depleted mice. We further demonstrate that CD137-stimulated helper NK cells expressed the high-affinity IL-2R and were hyperresponsive to IL-2. Taken together with previous findings that CD137 is a critical receptor for costimulation of T cells, our findings suggest that CD137 is a stimulatory receptor for NK cells involved in the crosstalk between innate and adaptive immunity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adjuvants, Immunologic / metabolism
  • Animals
  • Antigens, CD
  • Cytotoxicity, Immunologic*
  • Female
  • Growth Substances / metabolism
  • Injections, Intraperitoneal
  • Injections, Subcutaneous
  • Interleukin-2 / metabolism
  • Interleukin-2 / pharmacology*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Leukemia L1210
  • Lymphocyte Subsets / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Mice, Transgenic
  • Receptors, Interleukin-2 / biosynthesis
  • Receptors, Nerve Growth Factor / administration & dosage
  • Receptors, Nerve Growth Factor / biosynthesis
  • Receptors, Nerve Growth Factor / physiology*
  • Receptors, Tumor Necrosis Factor / administration & dosage
  • Receptors, Tumor Necrosis Factor / biosynthesis
  • Receptors, Tumor Necrosis Factor / physiology*
  • Signal Transduction / immunology*
  • Solubility
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Up-Regulation / immunology

Substances

  • Adjuvants, Immunologic
  • Antigens, CD
  • Growth Substances
  • Interleukin-2
  • Receptors, Interleukin-2
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9