Toll Pathway-Dependent Blockade of CD4
            <sup>+</sup>
            CD25
            <sup>+</sup>
            T Cell-Mediated Suppression by Dendritic Cells

Pasare, Chandrashekhar; Medzhitov, Ruslan

doi:10.1126/science.1078231

Cited by 1,891 publications

(1,517 citation statements)

References 26 publications

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“…In addition to delivering MyD88-dependent signals typical of most TLRs, TLR-3 can also trigger a non-MyD88-dependent signaling pathway that induces secretion of type I interferons (11), which have been particularly implicated in the development of autoimmunity (13). Furthermore, we have shown that TLR-3 but not TLR-5 induces high levels of IL-6 secretion; this is notable because IL-6 can block the suppressor activity of CD4ϩ,CD25ϩ T cells (14).…”

Section: Discussionmentioning

confidence: 70%

U1 RNA induces innate immunity signaling

Hoffman

Gazitt

Foecking

et al. 2004

Arthritis & Rheumatism

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Objective. The U1-70-kd RNP is a prominent target of autoimmunity in connective tissue diseases. In this study, we explored whether its endogenous ligand, U1 RNA, mediates a proimmune signal and may be immunogenic.Methods. We assayed the proliferation of control and MyD88-knockout splenocytes in response to in vitro-synthesized U1 RNA, and measured interleukin-6 (IL-6) and IL-8 secretion induced by U1 RNA in a human cell line competent for signaling through Tolllike receptor 3 (TLR-3) and TLR-5. Conclusion. U1 RNA is capable of inducing manifestations consistent with TLR-3 activation. The ability of U1 RNA (which has a substantial double-stranded secondary structure) to activate TLR-3 may contribute to the immunogenicity of the U1-70-kd autoantigen.Stimulation of innate immunity by native RNA molecules with a double-stranded secondary structure may help explain the high prevalence of autoimmunity to RNA binding proteins.

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Section: Discussionmentioning

confidence: 70%

U1 RNA induces innate immunity signaling

Hoffman

Gazitt

Foecking

et al. 2004

Arthritis & Rheumatism

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“…Studies have shown that TLR-activated DC can reverse Treg anergy, suggesting that this could override suppression and permit protective immunity towards pathogens [52,53] -10 [56]. This implies that microbial components are important to drive IL-10 production, which subsequently influence the development of regulatory T cells.…”

Section: Discussionmentioning

confidence: 99%

Impaired regulatory T cell function in germ‐free mice

et al. 2006

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Regulatory T cells (Treg) are crucial for the maintenance of tolerance to auto-antigens and harmless exogenous antigens. Here, we studied the role of the commensal microbiota for the development and function of Treg. CD4 + CD25 + T cells were obtained from peripheral lymph nodes (PLN) and mesenteric lymph nodes (MLN) of germ-free (GF) and conventional (conv) NMRI mice and tested for phenotype and functional suppressive capacity. CD4 + CD25 + T cells from GF mice showed a lower relative gene expression of fork head box p3 gene (Foxp3) and were not as potent suppressors in vitro as CD4 + CD25 + T cells from conv animals. Intracellular staining for Foxp3 and CTLA-4 revealed proportional and regional differences in putative Treg subsets between conv and GF mice. Fewer of the CD4 + CD25 + T cells in GF MLN expressed Foxp3 and CTLA-4, while the expression of these markers was similar amongst the CD4 + CD25 + T cells in PLN of conv and GF mice. The largest difference between conv and GF Treg was observed in the liver draining celiac lymph node, where GF mice had fewer putative Treg as compared to conv mice. We propose that the presence of a microbial flora favors the development of a fully functional Treg population. IntroductionRegulatory T cells down-regulate unwanted and exaggerated immune reactions to auto-antigens as well as innocuous environmental antigens. Different subsets of Treg have been defined. Natural CD4 + CD25 + Treg are positively selected for tissue-specific self-Ag in the thymus and exert their suppressive effect by cell-cell contact-dependent mechanisms [1]. Deficiency in the Treg population or neonatal thymectomy result in multiorgan autoimmune diseases [2][3][4][5][6][7][8]. Treg are characterized by a dense surface expression of CD25 (the a-chain of the IL-2-receptor), glucocorticoidinduced TNF receptor (GITR) and intracellular CTLA-4, however, these markers may be present on activated T cells. CD4 + CD25 + Tregs appear to be unique in transcribing the fork head box p3 gene (Foxp3) transcription factor [6,9], which enable their identification either with PCR are or newly developed mAb to the Foxp3 protein. Lack of a functional Foxp3 gene result in the severe autoimmune syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), characterized by organ-specific autoimmunity, colitis and high IgE levels [10,11]. Mice with spontaneous or induced mutations in the Foxp3 gene that impair Foxp3 expression fail to develop CD4 + CD25 + Treg and exhibit a syndrome similar to IPEX [5,6].Other subsets of Treg are induced in the periphery and are referred to as Th3 [12][13][14] and Tr1 cells [15][16][17][18][19] can also generate Treg. This implies that the state of the APC and the local cytokine milieu, e.g. in the normal gut where both IL-10 and TGF-b are abundant, can determine the outcome of an immune reaction, and that Treg are induced under these circumstances.The aim of this study was to investigate the phenotype and functionality of CD4 + CD25 + Treg from germ-free (GF) ...

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“…For instance, bacterial virulence factors from Bacillus anthracis impair in vivo DC function by disrupting intracellular signaling networks, thereby disarming adaptive immune responses [24]. On another level, TLR triggering on DC can block the suppressive effects of regulatory T cells by releasing specific cytokines [25]. It is possible that distinct TLR are triggered on DC by live and heat-killed bacteria.…”

Section: Discussionmentioning

confidence: 99%

Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes

et al. 2005

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Immunization of mice with live or heat-killed Listeria monocytogenes (HKLM) efficiently primes pathogen-specific CD8 + T cells. T lymphocytes primed by HKLM, however, undergo attenuated proliferation and do not fully differentiate. Thus, only infection with live bacteria induces long-term, CD8 + T cell-mediated protective immunity. In this study we demonstrate that live and heat-killed bacteria, while both associating with Mac-3 + CD11b hi cells, localize to distinct splenic areas following intravenous inoculation. While HKLM localize to the marginal zone and the splenic red pulp, live L. monocytogenes are carried to the T cell zone of splenic white pulp. Despite these differences, in vivo depletion of CD11c-expressing cells prevents priming of naive T cells by either HKLM or live L. monocytogenes. Analysis of CD11c hi dendritic cells (DC) reveals that infection with live L. monocytogenes induces higher levels of CD40, CD80 and CD86 expression than immunization with HKLM. Our results suggest that CD8 + T cell priming following HKLM immunization or live infection is mediated by DC and that the disparate outcomes of priming can be attributed to suboptimal conditioning of DC in the absence of live, cytosol-invasive bacteria.

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Toll Pathway-Dependent Blockade of CD4 ⁺ CD25 ⁺ T Cell-Mediated Suppression by Dendritic Cells

Cited by 1,891 publications

References 26 publications

U1 RNA induces innate immunity signaling

U1 RNA induces innate immunity signaling

Impaired regulatory T cell function in germ‐free mice

Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes

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Toll Pathway-Dependent Blockade of CD4 + CD25 + T Cell-Mediated Suppression by Dendritic Cells

Cited by 1,891 publications

References 26 publications

U1 RNA induces innate immunity signaling

U1 RNA induces innate immunity signaling

Impaired regulatory T cell function in germ‐free mice

Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes

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Toll Pathway-Dependent Blockade of CD4 ⁺ CD25 ⁺ T Cell-Mediated Suppression by Dendritic Cells