Expression and function of Toll-like receptors in T lymphocytes

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Toll-like receptors (TLRs) are widely expressed in the innate immune system. They recognize conserved microbial ligands such as bacterial lipopolysaccharide, lipopeptides or viral and bacterial RNA and DNA. TLRs play an essential role in innate immune responses and in the initiation of adaptive immune responses. However, certain TLRs are also expressed in T lymphocytes, and the respective ligands can directly modulate T cell function. TLR2, TLR3, TLR5 and TLR9 act as co-stimulatory receptors to enhance proliferation and/or cytokine production of T-cell receptor-stimulated T lymphocytes. In addition, TLR2, TLR5 and TLR8 modulate the suppressive activity of naturally occurring CD25+CD4+ regulatory T cells. The direct responsiveness of T lymphocytes to TLR ligands offers new perspectives for the immunotherapeutic manipulation of T cell responses.

Introduction

Toll-like receptors (TLRs) are pathogen recognition receptors that are used by the innate immune system to detect conserved pathogen-associated molecular patterns (PAMPs) of bacteria, parasites, fungi or viruses, and thus alert the immune system to the presence of infection. They are transmembrane proteins, the ligand-binding leucine-rich repeat domains of which interact with extracellular or membrane-enclosed (endosomal) intracellular PAMPs [1].

Signalling by the TLRs is initiated through the TLR signal transduction domains known as Toll/IL-1 receptor domains (TIRs), which can interact with cytoplasmic adaptor proteins including MyD88, TIRAP/MAL and TRIF. Signalling pathways activated by TLRs result either in the activation of the transcription factor NF-κB, with subsequent production of proinflammatory cytokines, chemokines, antimicrobial peptides and additional defense molecules, or in the activation of mitogen-activated protein kinases p38 and JNK [2]. Some TLRs recognize bacterial PAMPs, for example TLR4 recognizes lipopolysaccharide (LPS), TLR2 in combination with TLR1 or TLR6 as heterodimers recognize diacetylated or triacetylated bacterial lipopeptides, respectively, and TLR5 recognizes flagellin. In addition, TLR3 recognizes viral double-stranded RNA, mouse TLR7 and human TLR8 recognize single-stranded RNA, and TLR9 recognizes bacterial and viral DNA sequences that contain unmethylated CpG motifs [1, 2].

The localization of the latter group of TLRs (TLR3, 7, 8 and 9) is thought to be strictly intracellular, meaning that the ligands need to be internalized and transported to the endosome before signalling is initiated. TLRs are widely distributed and are expressed at varying levels in different tissues and cells. Generally, however, TLRs are expressed in epithelia and have specific roles in local immune defense [1]. Various TLRs are also expressed in lymphoid and myeloid cells, in particular in dendritic cells (DCs) in which they play a key role in the initiation of an adaptive immune response by inducing the maturation and cytokine production of DCs [3]. Recent studies indicate, however, that certain TLRs are also expressed in T lymphocytes. In this article, we review current knowledge regarding the expression and function of TLRs in specific T cell subsets.

Section snippets

Analysis at the mRNA level

The expression of TLR1–10 has been analyzed by quantitative PCR (qPCR) and flow cytometry (when antibodies are available) in purified T lymphocytes and in lymphoid tissue. A caveat to such experiments is the purity of isolated cell populations. Even a small percentage of contaminating non-T cells such as DCs might have a major impact in qPCR analyses. In human peripheral T cells isolated to >95% purity, low expression of TLR1–10 mRNA was detected by qPCR [4, 5, 6]. It is difficult to compare

Direct effects of TLR ligands on T cells

TLRs are crucial in the initiation of an adaptive immune response because they mediate PAMP-induced maturation of and cytokine secretion by DCs leading to enhanced antigen presentation, polarization of T cell responses and reversal of suppressive Treg activity [3, 25, 26, 27]. In addition, however, T cell functions can be directly influenced by TLRs expressed on T cells. With few exceptions, it appears that TLR signalling modulates T cell responses triggered by TCR stimulation rather than

Conclusions

In addition to cells of the innate immune system, cells of the adaptive immune system, including T lymphocytes, express certain TLRs and respond directly to corresponding ligands in concert with a TCR signal. This concept has immediate consequences for the regulation of cellular immune responses and for the control of suppressive regulatory T cell activity. Future studies should attempt to resolve apparent discrepancies (e.g. enhancement versus inhibition of suppressive Treg activity by TLR2

Update

Recently, convincing evidence for a direct co-stimulatory effect of TLR9 ligand CpG DNA on murine CD4+ T cells has been reported by Gelman et al. [44••]. Using CD4+ T cells from mice lacking the adaptor molecule MyD88 that have been reconstituted with MyD88, the authors showed that CpG oligonucleotides co-stimulate CD4+ T cell proliferation and IL-2 production in a phosphatidylinositol 3-kinase-dependent pathway. Importantly, they also demonstrated that MyD88 expression specifically in CD4+ T

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 415 A15, Ka 502/8-3). I thank Ottmar Janssen and Ruslan Medzhitov for helpful comments.

References (45)

  • K.A. Zarember et al.

    Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines

    J Immunol

    (2002)
  • A. Dolganiuc et al.

    Distinct Toll-like receptor expression in monocytes and T cells in chronic HCV infection

    World J Gastroenterol

    (2006)
  • G. Caron et al.

    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

    J Immunol

    (2005)
  • G. Peng et al.

    Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function

    Science

    (2005)
  • N.K. Crellin et al.

    Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells

    J Immunol

    (2005)
  • A. Mansson et al.

    Toll-like receptors in cellular subsets of human tonsil T cells: altered expression during recurrent tonsillitis

    Respir Res

    (2006)
  • I. Caramalho et al.

    Regulatory T cells selectively express Toll-like receptors and are activated by lipopolysaccharide

    J Exp Med

    (2003)
  • V. Sobek et al.

    Direct Toll-like receptor 2 mediated co-stimulation of T cells in the mouse system as a basis for chronic inflammatory joint disease

    Arthritis Res Ther

    (2004)
  • A.E. Gelman et al.

    Toll-like receptor ligands directly promote activated CD4+ T cell survival

    J Immunol

    (2004)
  • A. Cottalorda et al.

    TLR2 engagement on CD8 T cells lowers the threshold for optimal antigen-induced T cell activation

    Eur J Immunol

    (2006)
  • D. Wesch et al.

    Direct costimulatory effect of TLR3 ligand poly(I:C) on human γδ T lymphocytes

    J Immunol

    (2006)
  • E. Kress et al.

    Distinct gene expression in human Vδ1 and Vδ2 γδ T cells following non-TCR agonist stimulation

    Mol Immunol

    (2006)
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