Tumor-infiltrating Gammadelta T Cells Suppress T and Dendritic Cell Function via Mechanisms Controlled by a Unique Toll-Like Receptor Signaling Pathway

Immunity. 2007 Aug;27(2):334-48. doi: 10.1016/j.immuni.2007.05.020. Epub 2007 Jul 26.

Abstract

gammadelta T cells are important contributors to innate immunity against cancer, but their regulatory role in controlling immune responses remains largely unknown. Here we report that a dominant gammadelta1 T cell population among lymphocytes infiltrating breast tumors possessed a potent ability to suppress naive and effector T cell responses and to block the maturation and function of dendritic cells. Adoptive cotransfer experiments demonstrated their in vivo suppressive activity. However, their immunosuppressive activity could be reversed by human Toll-like receptor (TLR) 8 ligands both in vitro and in vivo. siRNA-mediated knockdown experiments revealed that MyD88, TRAF6, IKKalpha IKKbeta, and p38alpha molecules in gammadelta1 cells were required for these cells to respond to TLR8 ligands, whereas TAK1, JNK, and ERK molecules did not appear to be involved in functional regulation. These results provide new insights into the regulatory mechanisms of tumor-specific gammadelta T cells and identify a unique TLR8 signaling pathway linking to their functional regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / immunology*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Dendritic Cells / immunology
  • Female
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Immune Tolerance*
  • Ligands
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Male
  • Myeloid Differentiation Factor 88 / antagonists & inhibitors
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • Prostatic Neoplasms / immunology*
  • Receptors, Antigen, T-Cell, gamma-delta / analysis
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*
  • TNF Receptor-Associated Factor 6 / antagonists & inhibitors
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism
  • Toll-Like Receptor 8 / genetics
  • Toll-Like Receptor 8 / physiology*

Substances

  • Ligands
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • Receptors, Antigen, T-Cell, gamma-delta
  • TLR8 protein, human
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptor 8
  • I-kappa B Kinase
  • MAP Kinase Kinase Kinases