Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-gamma production by memory CD4+ T cells

J Immunol. 2005 Aug 1;175(3):1551-7. doi: 10.4049/jimmunol.175.3.1551.

Abstract

TLRs are involved in innate cell activation by conserved structures expressed by microorganisms. Human T cells express the mRNA encoding most of TLRs. Therefore, we tested whether some TLR ligands may modulate the function of highly purified human CD4+ T lymphocytes. We report that, in the absence of APCs, flagellin (a TLR5 ligand) and R-848 (a TLR7/8 ligand) synergized with suboptimal concentrations of TCR-dependent (anti-CD3 mAb) or -independent stimuli (anti-CD2 mAbs or IL-2) to up-regulate proliferation and IFN-gamma, IL-8, and IL-10 but not IL-4 production by human CD4+ T cells. No effect of poly(I:C) and LPS, ligands for TLR3 and TLR4, respectively, was detected. We also observed that CD4+CD45RO+ memory T cell responses to TLR ligands were more potent than those observed with CD4+CD45RA+ naive T cells. Moreover, among the memory T cells, CCR7- effector cells were more sensitive to TLR ligands than CCR7+ central memory cells. These data demonstrate for the first time a direct effect of TLR5 and TLR7/8 ligands on human T cells, and highlight an innate arm in T cell functions. They also suggest that some components from invading microorganisms may directly stimulate effector memory T cells located in tissues by up-regulating cytokine and chemokine production.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Proliferation* / drug effects
  • Cells, Cultured
  • Flagellin / metabolism
  • Flagellin / pharmacology*
  • Humans
  • Imidazoles / metabolism
  • Imidazoles / pharmacology*
  • Immunologic Memory* / drug effects
  • Interferon-gamma / biosynthesis*
  • Interleukin-10 / biosynthesis
  • Interleukin-2 / biosynthesis
  • Interleukin-8 / biosynthesis
  • Leukocyte Common Antigens / biosynthesis
  • Ligands
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology*
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Membrane Glycoproteins / physiology*
  • RNA, Messenger / biosynthesis
  • Receptors, CCR7
  • Receptors, Cell Surface / biosynthesis
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, Cell Surface / physiology*
  • Receptors, Chemokine / metabolism
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptor 5
  • Toll-Like Receptor 7
  • Toll-Like Receptors
  • Up-Regulation / drug effects
  • Up-Regulation / immunology

Substances

  • CCR7 protein, human
  • Imidazoles
  • Interleukin-2
  • Interleukin-8
  • Ligands
  • Membrane Glycoproteins
  • RNA, Messenger
  • Receptors, CCR7
  • Receptors, Cell Surface
  • Receptors, Chemokine
  • TLR3 protein, human
  • TLR4 protein, human
  • TLR5 protein, human
  • TLR7 protein, human
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptor 5
  • Toll-Like Receptor 7
  • Toll-Like Receptors
  • Flagellin
  • Interleukin-10
  • Interferon-gamma
  • Leukocyte Common Antigens
  • resiquimod