Peripheral Tolerance to a Nuclear Autoantigen: Dendritic Cells Expressing a Nuclear Autoantigen Lead to Persistent Anergic State of CD4+ Autoreactive T Cells After Proliferation

Kawahata, K.; Misaki, Yoshikata; Yamauchi, Michiko; Tsunekawa, Shinji; Setoguchi, Keigo; Miyazaki, Junichi; Yamamoto, Kazuhiko

doi:10.4049/jimmunol.168.3.1103

Cited by 11 publications

(18 citation statements)

References 62 publications

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“…Reduced responsiveness of CD4 + T cells involving impaired c-Jun phosphorylation has been described when Ag was transgenically expressed in DCs in vivo for prolonged time periods after the priming phase (34). Similarly, long-lasting presentation of low levels of nuclear Ags by DCs was required for the induction of T cell hyporesponsiveness (35).…”

Section: Discussionmentioning

confidence: 99%

Antigen Targeting to Plasmacytoid Dendritic Cells via Siglec-H Inhibits Th Cell-Dependent Autoimmunity

Loschko

Heink

Hackl

et al. 2011

The Journal of Immunology

101

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Plasmacytoid dendritic cells (PDCs) have been shown to present Ags and to contribute to peripheral immune tolerance and to Ag-specific adaptive immunity. However, modulation of adaptive immune responses by selective Ag targeting to PDCs with the aim of preventing autoimmunity has not been investigated. In the current study, we demonstrate that in vivo Ag delivery to murine PDCs via the specifically expressed surface molecule sialic acid binding Ig-like lectin H (Siglec-H) inhibits Th cell and Ab responses in the presence of strong immune stimulation in an Ag-specific manner. Correlating with sustained low-level MHC class II-restricted Ag presentation on PDCs, Siglec-H–mediated Ag delivery induced a hyporesponsive state in CD4+ T cells leading to reduced expansion and Th1/Th17 cell polarization without conversion to Foxp3+ regulatory T cells or deviation to Th2 or Tr1 cells. Siglec-H–mediated delivery of a T cell epitope derived from the autoantigen myelin oligodendrocyte glycoprotein to PDCs effectively delayed onset and reduced disease severity in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis by interfering with the priming phase without promoting the generation or expansion of myelin oligodendrocyte glycoprotein-specific Foxp3+ regulatory T cells. We conclude that Ag delivery to PDCs can be harnessed to inhibit Ag-specific immune responses and prevent Th cell-dependent autoimmunity.

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Section: Discussionmentioning

confidence: 99%

Antigen Targeting to Plasmacytoid Dendritic Cells via Siglec-H Inhibits Th Cell-Dependent Autoimmunity

Loschko

Heink

Hackl

et al. 2011

The Journal of Immunology

101

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“…We s.c. immunized Ld-nOVA mice and nontransgenic littermates with 100 g OVA in CFA at the base of the tail and then cultured the draining lymph node cells with various doses of OVA or OVA 323-339 dominant epitope (OVAp) 10 days after the immunization. The proliferative responses were greatly reduced in the Ld-nOVA mice in comparison with nontransgenic littermates, indicating that LdnOVA mice are tolerant to OVA (26).…”

Section: The Numbers Of Cd4mentioning

confidence: 92%

“…RAG2-deficient BALB/c mice and TCR ␣-chain-deficient C57BL/6 mice were purchased from Taconic Farms (Germantown, NY). Generation of Ld-nOVA transgenic mice has been described in another study (26). Briefly, chicken egg OVA cDNA (kindly provided by P. Chambon, Institut de Genetique et de Biologie Moleculaire et Cellulaire, Universite Louis Pasteur, Strasbourg, France) fused with the nuclear localization signal at the 3Ј end was subcloned into pLG-E, which had been produced by inserting a human E enhancer into the 5Ј end of the L d class I promoter of pLG-2 plasmid (27).…”

Section: Micementioning

confidence: 99%

Generation of CD4+CD25+ Regulatory T Cells from Autoreactive T Cells Simultaneously with Their Negative Selection in the Thymus and from Nonautoreactive T Cells by Endogenous TCR Expression

Kawahata

Misaki

Yamauchi

et al. 2002

The Journal of Immunology

Self Cite

223

163

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Normal T cell repertoire contains regulatory T cells that control autoimmune responses in the periphery. One recent study demonstrated that CD4+CD25+ T cells were generated from autoreactive T cells without negative selection. However, it is unclear whether, in general, positive selection and negative selection of autoreactive T cells are mutually exclusive processes in the thymus. To investigate the ontogeny of CD4+CD25+ regulatory T cells, neo-autoantigen-bearing transgenic mice expressing chicken egg OVA systemically in the nuclei (Ld-nOVA) were crossed with transgenic mice expressing an OVA-specific TCR (DO11.10). Ld-nOVA × DO11.10 mice had increased numbers of CD4+CD25+ regulatory T cells in the thymus and the periphery despite clonal deletion. In Ld-nOVA × DO11.10 mice, T cells expressing endogenous TCR αβ chains were CD4+CD25− T cells, whereas T cells expressing autoreactive TCR were selected as CD4+CD25+ T cells, which were exclusively dominant in recombination-activating gene 2-deficient Ld-nOVA × DO11.10 mice. In contrast, in DO11.10 mice, CD4+CD25+ T cells expressed endogenous TCR αβ chains, which disappeared in recombination-activating gene 2-deficient DO11.10 mice. These results indicate that part of autoreactive T cells that have a high affinity TCR enough to cause clonal deletion could be positively selected as CD4+CD25+ T cells in the thymus. Furthermore, it is suggested that endogenous TCR gene rearrangement might critically contribute to the generation of CD4+CD25+ T cells from nonautoreactive T cell repertoire, at least under the limited conditions such as TCR-transgenic models, as well as the generation of CD4+CD25− T cells from autoreactive T cell repertoire.

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“…CD4 ϩ T cells were isolated from spleens of mice immunized with 100 g of ovalbumin (OVA) emulsified with complete Freund's adjuvant after 14 days. CD4 ϩ T cells (4 ϫ 10 5 cells) were incubated with irradiated peritoneal macrophages (5 ϫ 10 5 cells) in 96-well plates at the indicated concentration of OVA in RPMI medium 1640 containing 10% FCS for 72 h. They were pulsed with 1 Ci (1 Ci ϭ 37 GBq) [ 3 H]thymidine for the final 12 h, and radioactivity was measured by liquid scintillation counting (30). For proliferation assay, primary epidermal keratinocytes (4 ϫ 10 4 cells) were plated on a type I collagen-precoated 96-well plate and cultured in the presence of 10 ng⅐ml Ϫ1 EGF, then pulsed with 0.5 Ci of [ 3 H]thymidine for the final 8 h, and radioactivity was measured by using liquid scintillation counting (29).…”

Section: Methodsmentioning

confidence: 99%

Dermatitis due to epiregulin deficiency and a critical role of epiregulin in immune-related responses of keratinocyte and macrophage

Shirasawa

Sugiyama

Baba

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Epidermal growth factor (EGF) family members, including epiregulin (EP), play a fundamental role in epithelial tissues; however, their roles in immune responses and the physiological role of EP remain to be elucidated. The skin has a versatile system of immune surveillance. Biologically active IL-1␣ is released to extracellular space upon damage from keratinocytes and is a major player in skin inflammation. Here, we show that EP is expressed not only in keratinocytes but also in tissue-resident macrophages, and that EP-deficient (EP ؊/؊ ) mice develop chronic dermatitis. Wound healing in the skin in EP ؊/؊ mice was not impaired in vivo, nor was the growth rate of keratinocytes from EP ؊/؊ mice different from that of WT mice in vitro. Of interest is that in WT keratinocytes, both IL-1␣ and the secreted form of EP induced down-regulation of IL-18 mRNA expression, which overexpression in the epidermis was reported to induce skin inflammation in mice, whereas the downregulation of IL-18 induced by IL-1␣ was impaired in EP ؊/؊ keratinocytes. Although bone marrow transfer experiments indicated that EP deficiency in non-bone-marrow-derived cells is essential for the development of dermatitis, production of proinflammatory cytokines by EP ؊/؊ macrophages in response to Toll-like receptor agonists was much lower, compared with WT macrophages, whose dysfunction in EP ؊/؊ macrophages was not compensated by the addition of the secreted form of EP. These findings, taken together, suggested that EP plays a critical role in immune͞inflammatory-related responses of keratinocytes and macrophages at the barrier from the outside milieu and that the secreted and membranebound forms of EP have distinct functions.T he system of epidermal growth factor (EGF) superfamily (1) and EGF receptor (EGFR) family, including EGFR (ErbB1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) (2), play a fundamental role in epithelial tissues. EGF family members, including EGF, transforming growth factor-␣, amphiregulin, heparinbinding EGF (HB-EGF), epiregulin (EP), and other members, regulate these receptors by inducing their homo-and͞or heterooligomerization (2, 3). EGF family members vary in their ability to activate distinct ErbB heterodimers, and this mechanism may, in part, account for the differences in their bioactivities (4-7).The membrane-anchored precursor of the EGF family is enzymatically processed externally to release a mature soluble form that acts as autocrine and͞or paracrine growth factor (8, 9), whereas some members of the EGF family act in the membrane-anchored form (8, 10). A bioactive transmembrane precursor, pro-HB-EGF, was suggested to induce growth inhibition or apoptosis rather than the proliferative response induced by soluble HB-EGF (10). EP (11-17) acts as an autocrine growth factor in normal human keratinocytes in vitro (15); however, its physiological role in vivo still remains to be elucidated.Keratinocytes in the epidermis play critical roles in the cutaneous immune-related responses (18) and contain biologically active ...

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Peripheral Tolerance to a Nuclear Autoantigen: Dendritic Cells Expressing a Nuclear Autoantigen Lead to Persistent Anergic State of CD4+ Autoreactive T Cells After Proliferation

Cited by 11 publications

References 62 publications

Antigen Targeting to Plasmacytoid Dendritic Cells via Siglec-H Inhibits Th Cell-Dependent Autoimmunity

Antigen Targeting to Plasmacytoid Dendritic Cells via Siglec-H Inhibits Th Cell-Dependent Autoimmunity

Generation of CD4+CD25+ Regulatory T Cells from Autoreactive T Cells Simultaneously with Their Negative Selection in the Thymus and from Nonautoreactive T Cells by Endogenous TCR Expression

Dermatitis due to epiregulin deficiency and a critical role of epiregulin in immune-related responses of keratinocyte and macrophage

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