Anti-CD3-activated killer T cells: Interleukin-6 modulates the induction of major histocompatibility complex-unrestricted cytotoxicity and the expression of genes coding for cytotoxic effector molecules

J Interferon Cytokine Res. 1997 Dec;17(12):727-37. doi: 10.1089/jir.1997.17.727.

Abstract

We have investigated the role of interleukin-6 (IL-6) in the induction of major histocompatibility complex (MHC)-unrestricted cytotoxicity, as well as granzyme B, perforin, and Fas ligand gene expression, following mouse T lymphocyte activation with anti-CD3 monoclonal antibody (mAb). The generation of anti-CD3-activated killer-T (AK-T) cells was inhibited when anti-IL-6 neutralizing mAb was added at initiation of culture but not 24 h later, indicating that IL-6 is involved at an early stage of AK-T cell development. However, AK-T cell induction in the presence of exogenous IL-6 did not result in enhanced cytotoxicity, suggesting that saturating levels of IL-6 are normally synthesized in AK-T cell cultures. The inhibitory effect of IL-6 neutralization on AK-T cell generation could not be attributed to a defect in AK-T cell proliferation or to an inability of AK-T cells to recognize and adhere to P815 tumor target cells. However, IL-2 synthesis and CD25 expression were downregulated in AK-T cell cultures performed in the presence of anti-IL-6 mAb. In addition, IL-6 neutralization resulted in decreased expression of granzyme B and perforin, but not Fas ligand, mRNA. Exogenous IL-2 (50 U/ml) added at initiation of culture completely reversed the inhibitory effect of anti-IL-6 mAb on AK-T cell development, restoring CD25 expression and tumoricidal activity, as well as granzyme B and perforin mRNA expression, to control levels. We conclude that IL-6 modulates AK-T cell induction through an IL-2-dependent mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD3 Complex / immunology*
  • Cell Line
  • Female
  • Gene Expression
  • Genetic Code
  • Granzymes
  • Interleukin-2 / physiology
  • Interleukin-6 / genetics
  • Interleukin-6 / physiology*
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation / immunology*
  • Major Histocompatibility Complex / immunology*
  • Membrane Glycoproteins / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • Receptors, Interleukin-2 / biosynthesis
  • Serine Endopeptidases / biosynthesis
  • T-Lymphocytes, Cytotoxic / immunology*

Substances

  • CD3 Complex
  • Interleukin-2
  • Interleukin-6
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Receptors, Interleukin-2
  • Perforin
  • Granzymes
  • Gzmb protein, mouse
  • Serine Endopeptidases