Toll-Like Receptor 8-Mediated Reversal of CD4
            <sup>+</sup>
            Regulatory T Cell Function

Peng, Gyangyong; Guo, Zhong; Kiniwa, Yukiko; Voo, Kui Shin; Peng, Weiyi; Fu, Tihui; Wang, Daniel; Li, Yanchun; Wang, Helen Yicheng; Wang, Rongfu

doi:10.1126/science.1113401

Cited by 693 publications

(630 citation statements)

References 25 publications

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“…To overcome this potentially significant hurdle, especially in active immunization using LMP1 as a target Ag, it would be necessary to inhibit such CD4 + regulatory T cell function and induce protective Th1 and cytotoxic response with the aid of polyguanosine nucleotides [46] or OK432 [47]. Besides, the most important rationale for immunotherapy targeting with LMP1 is, we believe, the evidence that EBV-infected malignant cells do process and present LMP1-derived peptides and are sensitive to cognate CTL.…”

Section: Discussionmentioning

confidence: 99%

Epstein‐Barr virus (EBV) latent membrane protein‐1‐specific cytotoxic T lymphocytes targeting EBV‐carrying natural killer cell malignancies

et al. 2006

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Epstein‐Barr virus (EBV)‐encoded latent membrane protein (LMP) 1 is a potential target for immunotherapy of some proportion of Hodgkin's disease cases, nasopharyngeal carcinomas, EBV‐associated natural killer (NK)/T lymphomas, and chronic active EBV infection (CAEBV). Since it is unknown whether EBV‐infected NK/T cells are susceptible to lysis by LMP1‐specific cytotoxic T lymphohcytes (CTL), we here tested the ability of mRNA‐transduced antigen‐presenting cells (APC) to stimulate rare LMP1‐specific CTL. A 43‐amino acid N‐terminal deletion mutant LMP1 (ΔLMP1) could be efficiently expressed in dendritic cells and CD40‐activated B cells upon mRNA electroporation. ΔLMP1‐expressing APC were found to stimulate LMP1‐specific CTL from a healthy donor and a CTL clone recognized a peptide, IIIILIIFI, presented by HLA‐A*0206 molecules. Processing and presentation of the antigenic peptide proved dependent on expression of an immunoproteasome subunit, low‐molecular‐weight protein‐7, as confirmed by RNA interference gene silencing. Furthermore, an EBV‐infected NK cell line derived from a patient with CAEBV, and another from an NK lymphoma with enforced HLA‐A*0206 expression, were specifically lysed by the CTL. Overall, these data suggest that immunotherapy targeting LMP1 in EBV‐associated NK lymphomas and CAEBV might serve as an alternative treatment modality.

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Section: Discussionmentioning

confidence: 99%

Epstein‐Barr virus (EBV) latent membrane protein‐1‐specific cytotoxic T lymphocytes targeting EBV‐carrying natural killer cell malignancies

et al. 2006

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Section: Introductionmentioning

confidence: 99%

“…Moreover, TLR agonists directly promote further TLR expression, survival and the function of NKT and gd T cells [11,12]. Regulatory T cells also possess functional TLR and TLR signals either positively or negatively modulate their suppressive ability [13][14][15].Naïve CD8 1 T cells can be differentiated into cytotoxic T-cell 1 (Tc1) in the presence of IL-12, which produces IFN-g and are required for host immunity against infection and tumours, or Tc2 by IL-4, which mainly secrete IL-4 and contribute to allergic responses [16]. It is known that LPS is a powerful adjuvant for CD8 1 T-cell activation [17,18].…”

mentioning

confidence: 99%

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

Komai-Koma¹,

Gilchrist²,

Xu³

2009

Eur J Immunol

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LPS comprises a major PAMP and is a key target of the immune system during bacterial infection. While LPS can be recognised by innate immune cells via the TLR4 complex, it is unknown whether T lymphocytes, especially CD8 1 T cells are also capable of doing so. We report here that naïve human CD8 1 T cells, after activation by TCR stimulation, express surface TLR4 and CD14. These activated CD8 1 T cells can then secrete high concentrations of IFN-c, granzyme and perforin in response to LPS. These effects can be specifically inhibited using siRNA for TLR4. Furthermore, LPS can synergise with IL-12 to polarise the CD8 1 T cells into cytotoxic T-cell 1 (Tc1) that produce IFN-c but not IL-4, with or without TCR activation. Moreover, CD8 1 CD45RO 1 memory T cells constitutively expressed TLR4 and markedly enhanced IFN-c production when stimulated with LPS. In contrast, activated murine CD8 1 T cells lack TLR4 and CD14 expression and fail to respond to LPS for proliferation and cytokine production. Thus, human but not murine CD8 1 T cells are able to directly recognise bacterial LPS via LPS receptor complex and TLR4 provides a novel signal for the activation of effector and memory human CD8 1 T cells.Key words: CD14 . CD8 1 T cells . Tc1 . LPS . TLR Supporting Information available online IntroductionLPS is an abundant glycolipid in the outer-membrane of Gramnegative bacteria [1][2][3]. It consists of hydrophobic lipid A, the o-polysaccharide chain and a core oligosaccharide [3][4][5]. LPS is perhaps the most well-studied microbial molecule due to its powerful immune activating properties, extremely stable nature and wide distribution in the environment [1][2][3]. It is the key molecule responsible for the bacteria-triggered inflammatory response resulting in organ failure and death [1][2][3]. LPS is also closely associated with pathogenesis of many inflammatory diseases [1][2][3][4]. Despite this, the proinflammatory effects of LPS when harnessed may be beneficial; its powerful effect on both innate and adaptive immunity may provide a new generation of immune adjuvants for vaccine development against infection and cancer [2-4]. Therefore, a clearer understanding of how host recognises LPS is fundamentally important.TLR are a group of evolutionarily developed pathogen-pattern recognition receptors that are widely distributed on immune cells [3,5]. At least ten members of the TLR family in humans have been identified. These recognise different microbial products from bacteria, virus, fungi and parasites [2][3][4]. Host cells recognise LPS via a receptor complex consisting of TLR4, CD14 and MD2 in which LPS only signals through TLR4 and triggers cellular activation and expression of inflammatory genes [2][3][4]. Since TLR was originally identified in Drosophila, which lacks an adaptive immune system, the initial belief was that recognition of pathogen products was a characteristic of innate cells bearing 1564TLR [5,6]. However, the role of T cells bearing TLR in pathogen recognition is less well understood.Growing evide...

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“…Ainsi, l'IR constitue un obstacle à l'immunotolérance du greffon via les ligands endogènes libérés par les tissus lésés qui vont activer les TLR (Toll-like receptor) et la réponse immunitaire innée [16]. Cette activation des voies des TLR inhiberait la fonction des cellules lymphocytaires régulatrices (Treg) [19]. Dans le contexte de la transplantation, limiter les effets de la conservation constitue un objectif primordial pour limiter le risque de rejet aigu et améliorer la survie du greffon [20].…”

Section: Qualité Du Greffon Et Ischémie Reperfusionunclassified