Cutting Edge: T Cells Respond to Lipopolysaccharide Innately via TLR4 Signaling

Zanin-Zhorov, Alexandra; Tal-Lapidot, Guy; Cahalon, Liora; Cohen-Sfady, Michal; Pevsner‐Fischer, Meirav; Lider, Ofer; Cohen, Irun R.

doi:10.4049/jimmunol.179.1.41

Cited by 102 publications

(81 citation statements)

References 28 publications

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“…We found that LPS could costimulate T cells to make IFN-␥ in the presence of IL-2 to the same on May 10, 2018 by guest http://iai.asm.org/ extent as bacterial infection in both CD4 ϩ and CD8 ϩ T cells. TLR4 expression on memory T cells has been reported (4) and, although stimulation via LPS alone does not result in proliferation nor cytokine production, T cells are able to respond to LPS via TLR4 by upregulating adherence to fibronectin and SOCS3 (39). Thus, LPS may be able to directly costimulate human T cells during B. pseudomallei infection, although LPS from B. pseudomallei has been described as less stimulatory (34).…”

Section: Vol 76 2008 B Pseudomallei Infection Costimulates T Cellsmentioning

confidence: 97%

Burkholderia pseudomallei Infection of T Cells Leads to T-Cell Costimulation Partially Provided by Flagellin

Lee

Sun

et al. 2008

Infect Immun

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Burkholderia pseudomallei is the causative agent of melioidosis. While adaptive immunity has been shown to be important for host resistance to B. pseudomallei, the direct interaction of the bacteria with adaptive immune cells such as T and B cells is not well known. To address this question, we infected Jurkat T cells, as well as human primary CD4؉ and CD8 ؉ T cells, with live B. pseudomallei. We found that live bacterial infection could costimulate T cells to produce interleukin-2 (IL-2) and gamma interferon (IFN-␥) in the presence of anti-CD3 cross-linking antibodies. Bacterial supernatant could also costimulate T cells, and this was due to the presence of flagellin in the supernatant. However, T cells infected with bacterial mutants lacking flagellin showed strong impairment in IL-2 but only a slight impairment in IFN-␥ production. When cross-linking of CD3 is replaced by IL-2, live bacterial infection was still able to costimulate human primary T cells to produce IFN-␥ and flagellin is only a minor ligand contributing to this costimulation. Thus, live B. pseudomallei could potentially costimulate T cells not only in an antigen-specific manner but also in a nonspecific manner through bystander activation via IL-2.Burkholderia pseudomallei is a gram-negative bacterium responsible for causing melioidosis, an infectious disease endemic in Southeast Asia and Northern Australia. The bacterium can invade and replicate in both cultured phagocytic (18, 28) and nonphagocytic cells (19). The type III secretion system 3 (TTSS3), also known as the Burkholderia secretion apparatus, enables B. pseudomallei to escape from the endosome into the cytoplasm of infected cells (29). Furthermore, the BimA protein found on one pole of the bacteria helps to facilitate intracellular spread by the formation of actin comet tails (30). These characteristics of the bacterium could help it to survive intracellularly. Upon phagocytosis by macrophages, B. pseudomallei is able to activate the suppressor of cytokine signaling 3 (SOCS3) and cytokine-inducible Src homology 2-containing protein, resulting in a decrease in the gamma interferon (IFN-␥) signaling response (9). We had previously shown that B. pseudomallei infection of monocytes, macrophages, and dendritic cells induced caspase-1-dependent cell death (32). The interference with host innate immune cells such as macrophages could have a profound impact on the innate immune response to bacteria, as well as on the development of the adaptive immune response.The interaction of B. pseudomallei with other immune cells, particularly those from the adaptive immune response such as T and B cells, is not well known. It has been shown that patients surviving melioidosis developed a cell-mediated immune response (20) and, in mice, B. pseudomallei-specific CD4 T cells are important for host resistance in adaptive immunity (16). This means that the ability of the host to develop a robust T-cell response is likely critical in controlling the infection, and there is a possibility that bacteria could ...

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Section: Vol 76 2008 B Pseudomallei Infection Costimulates T Cellsmentioning

confidence: 97%

Burkholderia pseudomallei Infection of T Cells Leads to T-Cell Costimulation Partially Provided by Flagellin

Lee

Sun

et al. 2008

Infect Immun

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“…CD4 T cell effector functions (as measured by CD40L and IFN-␥) were not significantly induced or enhanced by MPL in this present study. In some studies, T cell responses to TLR4 agonists have been observed, such as increased adherence and Ca 2ϩ mobilization, but these measures are not necessarily indicators of Ag-independent T cell activation (25,51,52). Therefore, it is likely that the superior adjuvant activity of AS04 resulted from APC-mediated activation of T cells and subsequent B cell activation.…”

Section: How Does As04 Enhance Ab Response Compared With Aluminum Hydmentioning

confidence: 99%

AS04, an Aluminum Salt- and TLR4 Agonist-Based Adjuvant System, Induces a Transient Localized Innate Immune Response Leading to Enhanced Adaptive Immunity

Didierlaurent

Morel

Lockman

et al. 2009

The Journal of Immunology

615

471

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Adjuvant System 04 (AS04) combines the TLR4 agonist MPL (3-O-desacyl-4′-monophosphoryl lipid A) and aluminum salt. It is a new generation TLR-based adjuvant licensed for use in human vaccines. One of these vaccines, the human papillomavirus (HPV) vaccine Cervarix, is used in this study to elucidate the mechanism of action of AS04 in human cells and in mice. The adjuvant activity of AS04 was found to be strictly dependent on AS04 and the HPV Ags being injected at the same i.m. site within 24 h of each other. During this period, AS04 transiently induced local NF-κB activity and cytokine production. This led to an increased number of activated Ag-loaded dendritic cells and monocytes in the lymph node draining the injection site, which further increased the activation of Ag-specific T cells. AS04 was also found to directly stimulate those APCs in vitro but not directly stimulate CD4+ T or B lymphocytes. These AS04-induced innate responses were primarily due to MPL. Aluminum salt appeared not to synergize with or inhibit MPL, but rather it prolonged the cytokine responses to MPL at the injection site. Altogether these results support a model in which the addition of MPL to aluminum salt enhances the vaccine response by rapidly triggering a local cytokine response leading to an optimal activation of APCs. The transient and confined nature of these responses provides further supporting evidence for the favorable safety profile of AS04 adjuvanted vaccines.

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“…In some cases lipopolysaccharide (LPS) (recognized by TLR-4) was reported to stimulate the activation of protein kinase C in CD3 + T cells 53 and perforin production in a subset of CD4 + T cells in patients with ankylosing spondylitis. 54 Moreover, Fukata et al 36 found that LPS-stimulated proliferation of T-effector cells was dependent on Myd88.…”

Section: Toll-like Receptor Engagement Affects Cd4 + T-effector and Tmentioning

confidence: 99%

The role of T‐regulatory cells and Toll‐like receptors in the pathogenesis of human inflammatory bowel disease

Himmel¹,

Hardenberg²,

Piccirillo³

et al. 2008

Immunology

131

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SummaryTwo related chronic inflammatory diseases, Crohn's disease and ulcerative colitis, are together often referred to as inflammatory bowel disease (IBD). Current treatment options are not curative, and patients face lifelong therapy and debilitation. IBD is thought to be the product of a combination of genetic and environmental factors that result in the abnormal regulation of immune responses. Experimental models have demonstrated that normal CD4 + T-regulatory (Treg) cell responses and commensal bacteria are required for the maintenance of gut immune homeostasis. Recent evidence that CD4 + T cells express Toll-like receptors (TLRs) and respond directly to TLR ligands, suggests that signals from commensal bacteria may directly affect T-cell responses in the gut. In this review, we focus on evidence that defects in Treg cells may underlie IBD in humans. In addition, we discuss evidence that direct signaling via TLRs to T cells can affect IBD and that T-cell-dependent responses to bacterial proteins, such as flagellin, are central to the aetiology of this disease.

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Cutting Edge: T Cells Respond to Lipopolysaccharide Innately via TLR4 Signaling

Cited by 102 publications

References 28 publications

Burkholderia pseudomallei Infection of T Cells Leads to T-Cell Costimulation Partially Provided by Flagellin

Burkholderia pseudomallei Infection of T Cells Leads to T-Cell Costimulation Partially Provided by Flagellin

AS04, an Aluminum Salt- and TLR4 Agonist-Based Adjuvant System, Induces a Transient Localized Innate Immune Response Leading to Enhanced Adaptive Immunity

The role of T‐regulatory cells and Toll‐like receptors in the pathogenesis of human inflammatory bowel disease

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