Direct Toll-like Receptor 2 Mediated Co-Stimulation of T Cells
Direct Toll-like Receptor 2 Mediated Co-Stimulation of T Cells
The pathogenesis of chronic inflammatory joint diseases such as adult and juvenile rheumatoid arthritis and Lyme arthritis is still poorly understood. Central to the various hypotheses in this respect is the notable involvement of T and B cells. Here we develop the premise that the nominal antigen-independent, polyclonal activation of preactivated T cells via Toll-like receptor (TLR)-2 has a pivotal role in the initiation and perpetuation of pathogen-induced chronic inflammatory joint disease. We support this with the following evidence. Both naive and effector T cells express TLR-2. A prototypic lipoprotein, Lip-OspA, from the etiological agent of Lyme disease, namely Borrelia burgdorferi, but not its delipidated form or lipopolysaccharide, was able to provide direct antigen-nonspecific co-stimulatory signals to both antigen-sensitized naive T cells and cytotoxic T lymphocyte (CTL) lines via TLR-2. Lip-OspA induced the proliferation and interferon (IFN)-γ secretion of purified, anti-CD3-sensitized, naive T cells from C57BL/6 mice but not from TLR-2-deficient mice. Induction of proliferation and IFN-γ secretion of CTL lines by Lip-OspA was independent of T cell receptor (TCR) engagement but was considerably enhanced after suboptimal TCR activation and was inhibitable by monoclonal antibodies against TLR-2.
Chronic inflammatory joint diseases (CIJDs) such as adult and juvenile rheumatoid arthritis and Lyme arthritis were first considered to be diseases caused and perpetuated by autoimmune processes, including the production of autoantibodies, immune complexes and/or autoreactive T cells. Recently, T cells have attracted most attention, and their activities, together with an autonomous role for the synovial lining cells, are now thought to be responsible for initiating and sustaining the inflammation. The re-emergence of the notion that cells of the innate immune system are essential in generating and perpetuating an immune response has focused attention on the involvement of these cells in chronic inflammatory disorders too.
The question of how the immunopathological processes are set off remains controversial. One leading cause seems to be microbial infection. Microbes are recognized not only by T and B cells of the adaptive immune system with their highly specific, monospecific receptors, but also by other cell types that use germline-encoded receptors to interact with microbes. For instance, conserved structural features of molecular determinants on pathogens, termed pathogen-associated molecular patterns, such as lipopolysaccharide (LPS), flagellin, peptidoglycans, microbial DNA and bacterial lipoproteins, are recognized by a set of germline-encoded receptors on host cells, the Toll-like receptor (TLR) family. These TLRs are crucial in sensing infections, in the induction of antimicrobial genes and for the control of innate and adaptive immunity. Recent observations have shown that TLRs are expressed not only by cells of the innate immune system but also by cells of the adaptive immune system, including B cells and T cells. Ligands for TLRs are found in rheumatoid synovium and are involved in the pathogenesis and severity of inflammatory arthritis.
T cells of multiple specificities, including self-specificities, are a frequent finding in inflammatory joint diseases such as Lyme arthritis and rheumatoid arthritis. At present, two mechanisms by which individual microbes induce disease-promoting T cells are in vogue: one is antigen-specific, the other antigen-nonspecific.
Antigen-specific activation, termed epitope mimicry, predicts that during infection T cells are activated that recognize both a microbial antigen and a related self peptide, with the consequence that these T cells would eventually crossreact with host tissue and result in its destruction. The antigen-nonspecific theory predicts that during infection T cells with any specificity, including non-crossreactive autoreactive T cells, can develop into effector cells in inflammatory microenvironments, thereby contributing to tissue destruction. These normally quiescent T cells need to be activated (that is, made competent) by processes that are independent of particular classical (that is, MHC-I-defined) microbial antigenic determinants and that can be elicited via a multitude of mechanisms, termed bystander activation.
In the two-signal model of lymphocyte activation, optimal activation requires a specific interaction of the antigen (peptide–MHC complex for T cells, antigen as such for B cells) with the T cell receptor (TCR) and B cell receptor complex, respectively (signal 1) and additional co-stimulatory signals (signal 2). For T cells, signal 2 is normally delivered by a dedicated set of receptor–ligand interactions between the antigen-presenting cell (APC) and the T cell, but it can apparently also be delivered by other cell-surface receptor types such as cytokine receptors and extracellular matrix receptors and by receptors that recognize microbial (cell wall) products. Of particular relevance is co-stimulation in B cell physiology: LPS, a constituent of the outer cell wall of Gram-negative bacteria, has long been known as a polyclonal B cell stimulator and, in the presence of interleukin (IL)-4, as an inducer of differentiation. In this function, LPS can replace a CD40-derived signal and induce class switch recombination. The receptor for LPS is TLR-4.
Here we have investigated whether a prototype outer surface lipoprotein, namely OspA of Borrelia burgdorferi, the causative agent of Lyme arthritis, is able to directly activate antigen-sensitized naive and/or effector T cells from mice by binding to its nominal receptor, TLR-2. For this purpose we used mouse strains with deficiencies for either TLR-2 (TLR-2) or TLR-4 (TLR-4).
The pathogenesis of chronic inflammatory joint diseases such as adult and juvenile rheumatoid arthritis and Lyme arthritis is still poorly understood. Central to the various hypotheses in this respect is the notable involvement of T and B cells. Here we develop the premise that the nominal antigen-independent, polyclonal activation of preactivated T cells via Toll-like receptor (TLR)-2 has a pivotal role in the initiation and perpetuation of pathogen-induced chronic inflammatory joint disease. We support this with the following evidence. Both naive and effector T cells express TLR-2. A prototypic lipoprotein, Lip-OspA, from the etiological agent of Lyme disease, namely Borrelia burgdorferi, but not its delipidated form or lipopolysaccharide, was able to provide direct antigen-nonspecific co-stimulatory signals to both antigen-sensitized naive T cells and cytotoxic T lymphocyte (CTL) lines via TLR-2. Lip-OspA induced the proliferation and interferon (IFN)-γ secretion of purified, anti-CD3-sensitized, naive T cells from C57BL/6 mice but not from TLR-2-deficient mice. Induction of proliferation and IFN-γ secretion of CTL lines by Lip-OspA was independent of T cell receptor (TCR) engagement but was considerably enhanced after suboptimal TCR activation and was inhibitable by monoclonal antibodies against TLR-2.
Chronic inflammatory joint diseases (CIJDs) such as adult and juvenile rheumatoid arthritis and Lyme arthritis were first considered to be diseases caused and perpetuated by autoimmune processes, including the production of autoantibodies, immune complexes and/or autoreactive T cells. Recently, T cells have attracted most attention, and their activities, together with an autonomous role for the synovial lining cells, are now thought to be responsible for initiating and sustaining the inflammation. The re-emergence of the notion that cells of the innate immune system are essential in generating and perpetuating an immune response has focused attention on the involvement of these cells in chronic inflammatory disorders too.
The question of how the immunopathological processes are set off remains controversial. One leading cause seems to be microbial infection. Microbes are recognized not only by T and B cells of the adaptive immune system with their highly specific, monospecific receptors, but also by other cell types that use germline-encoded receptors to interact with microbes. For instance, conserved structural features of molecular determinants on pathogens, termed pathogen-associated molecular patterns, such as lipopolysaccharide (LPS), flagellin, peptidoglycans, microbial DNA and bacterial lipoproteins, are recognized by a set of germline-encoded receptors on host cells, the Toll-like receptor (TLR) family. These TLRs are crucial in sensing infections, in the induction of antimicrobial genes and for the control of innate and adaptive immunity. Recent observations have shown that TLRs are expressed not only by cells of the innate immune system but also by cells of the adaptive immune system, including B cells and T cells. Ligands for TLRs are found in rheumatoid synovium and are involved in the pathogenesis and severity of inflammatory arthritis.
T cells of multiple specificities, including self-specificities, are a frequent finding in inflammatory joint diseases such as Lyme arthritis and rheumatoid arthritis. At present, two mechanisms by which individual microbes induce disease-promoting T cells are in vogue: one is antigen-specific, the other antigen-nonspecific.
Antigen-specific activation, termed epitope mimicry, predicts that during infection T cells are activated that recognize both a microbial antigen and a related self peptide, with the consequence that these T cells would eventually crossreact with host tissue and result in its destruction. The antigen-nonspecific theory predicts that during infection T cells with any specificity, including non-crossreactive autoreactive T cells, can develop into effector cells in inflammatory microenvironments, thereby contributing to tissue destruction. These normally quiescent T cells need to be activated (that is, made competent) by processes that are independent of particular classical (that is, MHC-I-defined) microbial antigenic determinants and that can be elicited via a multitude of mechanisms, termed bystander activation.
In the two-signal model of lymphocyte activation, optimal activation requires a specific interaction of the antigen (peptide–MHC complex for T cells, antigen as such for B cells) with the T cell receptor (TCR) and B cell receptor complex, respectively (signal 1) and additional co-stimulatory signals (signal 2). For T cells, signal 2 is normally delivered by a dedicated set of receptor–ligand interactions between the antigen-presenting cell (APC) and the T cell, but it can apparently also be delivered by other cell-surface receptor types such as cytokine receptors and extracellular matrix receptors and by receptors that recognize microbial (cell wall) products. Of particular relevance is co-stimulation in B cell physiology: LPS, a constituent of the outer cell wall of Gram-negative bacteria, has long been known as a polyclonal B cell stimulator and, in the presence of interleukin (IL)-4, as an inducer of differentiation. In this function, LPS can replace a CD40-derived signal and induce class switch recombination. The receptor for LPS is TLR-4.
Here we have investigated whether a prototype outer surface lipoprotein, namely OspA of Borrelia burgdorferi, the causative agent of Lyme arthritis, is able to directly activate antigen-sensitized naive and/or effector T cells from mice by binding to its nominal receptor, TLR-2. For this purpose we used mouse strains with deficiencies for either TLR-2 (TLR-2) or TLR-4 (TLR-4).
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