Direct Stimulation of Human T Cells via TLR5 and TLR7/8: Flagellin and R-848 Up-Regulate Proliferation and IFN-γ Production by Memory CD4+ T Cells

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-γ, 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.

Direct recognition of LPS by human but not murine CD8+ T cells via TLR4 complex

“…The present studies suggest that TLR4 signals directly drive Tc1 development in the presence of TCR or IL-12 signals. While the mechanism is still unclear and currently under investigation, this is in agreement with the previous findings that BLP preferentially promotes human and murine Th1 but not Th2 cell differentiation [7,8] and that TLR agonists selectively stimulate IFN-g but not IL-4 production by human gd T cells [9,10,12]. Our results therefore support current evidence and suggest the existence of a novel type I T-cell development pathway by directly recognising PAMP via TLRs on T cells.…”

“…This was subsequently confirmed in mice [8]. Furthermore, human and murine memory T cells constitutively express surface TLRs and directly recognise TLR agonists [7,9,10]. Moreover, TLR agonists directly promote further TLR expression, survival and the function of NKT and gd T cells [11,12].…”

“…Growing evidence suggests that T cells participate in immune microbial surveillance [7][8][9][10]. We reported for the first time that human CD4 1 T cells express functional TLR2 and that TLR2 signals directly promote T-cell function [7].…”

“…3c). Given the general effect on all types of T cells, the signal via TLR perhaps represents a previously unrecognised (fourth) signal for T-cell activation, differentiation, survival and memory [7][8][9][10][11][12]. Eur.…”

The TLR7 agonists imiquimod and gardiquimod improve DC-based immunotherapy for melanoma in mice

“…5,13 The major benefit of TLR7/8 agonists is that they not only activate antigen-presenting cells, [14][15][16] but also promote activation of T and NK cells and inhibit regulatory T cell function. 13,[17][18][19][20] Moreover, TLR7/8 ligands have been shown to directly affect some tumor cells by inducing apoptosis and sensitizing tumor cells to killing mediated by CTLs and chemotherapeutic agents. 21,22 However, these effects depend on the kinds of TLR7/8 agonists used and the type of tumor being treated.…”