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.
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.
Caron
Gersende
G
Unité Mixte Institut National de la Santé et de la Recherche Médicale 564, University Hospital, Angers, France.
Duluc
Dorothée
D
Frémaux
Isabelle
I
Jeannin
Pascale
P
David
Catherine
C
Gascan
Hugues
H
Delneste
Yves
Y
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005408:Flagellin / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D007156:Immunologic Memory / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D054400:Receptors, CCR7; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019707:Receptors, Chemokine / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
C515370:CCR7 protein, human; D007093:Imidazoles; D007376:Interleukin-2; D016209:Interleukin-8; D008024:Ligands; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D054400:Receptors, CCR7; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; C495344:TLR3 protein, human; C495345:TLR4 protein, human; C495346:TLR5 protein, human; C495348:TLR7 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; D005408:Flagellin; D016753:Interleukin-10; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; C402365:resiquimod