Insights into the role of Toll-like receptors in modulation of T cell responses

Abstract

The innate immune receptors, such as Toll-like receptors (TLRs), are intimately involved in the early sensing of invading microorganisms or their structural components. Engagement of TLRs with their ligands results in activation of several downstream intracellular pathways leading to activation of innate and adaptive immune system cells. It was initially thought that TLRs are primarily expressed by antigen-presenting cells (APCs), such as macrophages and dendritic cells, and that interactions between microbial ligands and TLRs in these cells will indirectly result in activation of cells of the adaptive immune system, especially T cells. However, it has now become evident that TLRs are also expressed by various T cell subsets, such as conventional αβT cells, regulatory T cells, and γδT cells as well as natural killer T cells. Importantly, it appears that at least in some of these T cell subsets, TLRs are functionally active, because stimulation of these cells with TLR agonists in the absence of APCs results in exertion of effector or regulatory functions of T cells. The present review attempts to summarize the recent findings related to TLR expression in different T cell subsets and the direct role of TLRs in the induction and regulation of T cell responses, including those responses that occur at mucosal surfaces. In addition, the potential use of TLR agonists for steering T cell responses as a prophylactic or therapeutic strategy in the context of infectious, allergic or autoimmune diseases is explored.

The parasitic helminth product ES‐62 suppresses pathogenesis in collagen‐induced arthritis by targeting the interleukin‐17–producing cellular network at multiple sites

“…ES-62-mediated suppression of the resultant IL-17 response therefore likely reflects not only the fact that TLRs can be expressed by most T cell subsets, but also the fact that TLR agonists (e.g., for TLR-3, -5, -7, and -9) can modulate Teff or Treg cell responses in the absence of antigen-presenting cells (for review, see ref. 27) and LPS/TLR-4 signaling can both induce and enhance IL-23-stimulated IL-17 release from Th17 cells differentiated in vitro (28).…”

Lipopolysaccharide directly stimulates Th17 differentiation in vitro modulating phosphorylation of RelB and NF-κB1

“…It was initially thought that TLRs are preferentially expressed in innate immune cells, such as macrophages and dendritic cells, and activation of these cells by the interaction of a TLR and its ligand indirectly leads to the activation of cells of the adaptive immune system, especially T cells [3][4][5]. However, it is evident that some of TLRs are expressed in various subsets of ␣␤T cells as well as ␥␦T cells [6,7]. TLR1-9 are expressed in naïve T cells in mice while TLR1, 2, 3, 4, 5, 7 and 9 mRNA were detected in human peripheral blood T cells.…”

Modulation of γδ T cell responses by TLR ligands

“…In recent years, it has been observed that TLR expression is not restricted to the innate immune system. TLR were detected in B cells as well as in T cells and in their subpopulations [14,15,33]. Recent studies (as described below) identified TLR expression in cd T cells possibly playing an important role in early immune responses of cd T cells against different pathogens.…”

“…TLR sense diverse pathogen-associated molecular patterns (PAMP), e.g., lipid-containing ligands, proteinaceous ligands, and nucleic acid ligands [12]. Besides their direct effects on cells of the innate immunity such as dendritic cells (DC) and NK cells, TLR have also been shown to co-stimulate TCR-activated human T cells [13][14][15]. In cd T cells, TLR1/TLR2, TLR2/TLR6, TLR3, and TLR5 ligands induce an enhanced production of cytokines and chemokines and an up-regulation of activation markers [16,17].…”