Oral Administration of Hapten Inhibits In Vivo Induction of Specific Cytotoxic CD8+ T Cells Mediating Tissue Inflammation: A Role for Regulatory CD4+ T Cells

Desvignes, Cyril; Etchart, Nathalie; Kehren, Jeanne; Akiba, Itoshi; Nicolas, Jean‐François; Kaiserlian, Dominique

doi:10.4049/jimmunol.164.5.2515

Cited by 54 publications

(59 citation statements)

References 35 publications

(34 reference statements)

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“…30 Among cosignal pathways, CD80/CD86-CTLA-4 and B7-DC (PD-L2)-PD-1 have been shown to contribute to oral tolerance regulation. 31,[46][47][48][49] Our current studies demonstrated that B7-H1/CD80 interaction also plays a crucial role in the induction and maintenance of oral tolerance ( Figure 5). This notion could be supported by recent reports that B7-H1 is highly expressed on CD11c ϩ CD8␣ Ϫ DC in mesenteric LN, which are a vital mediator for oral tolerance.…”

Section: Discussionmentioning

confidence: 58%

B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance

Park

Omiya

Matsumura

et al. 2010

Blood

290

237

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T-cell tolerance is the central program that prevents harmful immune responses against self-antigens, in which inhibitory PD-1 signal given by B7-H1 interaction plays an important role. Recent studies demonstrated that B7-H1 binds CD80 besides PD-1, and B7-H1/CD80 interaction also delivers inhibitory signals in T cells. However, a role of B7-H1/CD80 signals in regulation of T-cell tolerance has yet to be explored. We report here that attenuation of B7-H1/CD80 signals by treatment with anti-B7-H1 monoclonal antibody, which specifically blocks B7-H1/CD80 but not B7-H1/PD-1, enhanced T-cell expansion and prevented T-cell anergy induction. In addition, B7-H1/CD80 blockade restored Ag responsiveness in the previously anergized T cells. Experiments using B7-H1 or CD80-deficient T cells indicated that an inhibitory signal through CD80, but not B7-H1, on T cells is responsible in part for these effects. Consistently, CD80 expression was detected on anergic T cells and further up-regulated when they were reexposed to the antigen (Ag). Finally, blockade of B7-H1/CD80 interaction prevented oral tolerance induction and restored T-cell responsiveness to Ag previously tolerized by oral administration. Taken together, our findings demonstrate that the B7-H1/CD80 pathway is a crucial regulator in the induction and maintenance of T-cell tolerance. (Blood. 2010;116(8): 1291-1298) Introduction B7-H1 (CD274, PD-L1), a transmembrane glycoprotein belonging to immunoglobulin (Ig) superfamily molecule, plays an integral role in the regulation of immune tolerance and homeostasis. 1 Mice deficient of B7-H1 gene or wild-type mice treated with anti-B7-H1 blocking monoclonal antibody (mAb) exhibit exacerbated autoimmune phenotypes associated with an activation of self-reactive CD4 ϩ and CD8 ϩ T cells. [2][3][4][5] Tolerogenic functions of B7-H1 are dependent on its expression on hematopoietic or parenchymal cells, and mediated by its interaction with PD-1 receptor. 6-8 PD-1 is inducibly expressed on T cells after activation and delivers coinhibitory signals via immunoreceptor tyrosine-based switch motif in the cytoplasmic domain. 9,10 PD-1 signal interferes with phosphatidylinositol-3-kinase (PI3K) activity and subsequently inhibits interleukin-2 (IL-2) production, which eventually renders T cells anergic. 11 The mice deficient of PD-1 gene spontaneously develop autoimmune phenotypes, and single nucleotide polymorphisms of human PD-1 gene are associated with an increased risk of autoimmune diseases. [12][13][14][15][16] Recent studies by Butte et al discovered that B7-H1 interacts with CD80 (B7-1) in addition to PD-1. 17,18 In vitro studies using CD4ϩ T cells deficient of PD-1, CD28, and/or CTLA-4 indicated that B7-H1/CD80 interaction delivers bidirectional inhibitory signals to T cells. 17 These findings are consistent with previous observations implicating the presence of non-PD-1 receptor(s) of B7-H1. For instance, when the B7-H1/PD-1 interaction is blocked in models of T-cell tolerance, the effects of anti-B7-H1 antagonistic mAb in rest...

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Section: Discussionmentioning

confidence: 58%

B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance

Park

Omiya

Matsumura

et al. 2010

Blood

290

237

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“…In addition, in vivo depletion of CD25 ϩ T cells by specific antibody treatment impaired oral tolerance in normal C57BL/6 mice, although not completely as compared with anti-CD4 mAb depletion. 30 This could be explained by either (1) incomplete depletion of CD4 ϩ CD25 ϩ cells, especially from tissues such as the intestine, (2) concomitant depletion of activated CD8 ϩ effectors that have up-regulated CD25, or (3) the ability of CD4 ϩ CD25 Ϫ cells to exert some level of regulation, as reported in other models. 21,[36][37][38] Indeed, CD4 ϩ CD25 Ϫ cells were found to inhibit wasting or autoimmune disease in lymphopenic host to the same extent as CD4 ϩ CD25 ϩ cells.…”

Section: Discussionmentioning

confidence: 93%

“…Likewise, our previous studies of oral tolerance in the model of CHS showed that even when mice were double sensitized with 2 non-cross-reacting haptens (ie, DNFB and OXA) to generate effector cells specific for both, tolerance was induced exclusively by feeding with the same hapten as the one used for challenge. 30 It is possible that hapten feeding activates and/or expands antigen-specific CD4 ϩ CD25 ϩ T cells recognizing complexes of MHC class II/hapten-modified peptides. Alternatively, the apparent antigen specificity of T-cell regulation may relate to the fact that the APCs may simultaneously present the oral hapten to CD8 ϩ T cells and activate regulatory CD4 ϩ CD25 ϩ T cells via self-peptide/MHC class II complexes.…”

Section: Discussionmentioning

confidence: 99%

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Innate CD4+CD25+ regulatory T cells are required for oral tolerance and inhibition of CD8+ T cells mediating skin inflammation

Dubois

Chapat

Goubier

et al. 2003

Blood

Self Cite

162

155

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IntroductionOral tolerance has long been recognized as a physiologic mechanism of immune unresponsiveness to dietary antigens and bacterial microflora antigens, which maintain tissue integrity by preventing harmful delayed-type hypersensitivity (DTH) responses in the intestine and may also limit the efficiency of oral vaccination. Indeed, antigen encounter in the intestine triggers an active inhibitory process preventing the onset of CD4 ϩ and CD8 ϩ T-cell antigen-specific immune responses to subsequent systemic immunization with the same antigen (reviewed in Garside and Mowat 1 ). Several mechanisms have been proposed to explain peripheral tolerance induced by antigen feeding. These include anergy 2,3 or deletion of antigen-specific T cells, 4,5 immune deviation to Th2-biased immune response, and induction of regulatory Th3 (transforming growth factor ␤ [TGF␤]-producing) cells. 6,7 The naturally occurring regulatory subset of CD4 ϩ CD25 ϩ T cells accounting for 5% to 10% of peripheral CD4 ϩ T cells has been extensively reported to exert potent immunosuppressive function in vivo and in vitro toward CD4 ϩ T-cell effectors 8 and may represent regulatory T cells responsible for orally induced peripheral tolerance. Indeed, CD4 ϩ CD25 ϩ T cells, which arise from the thymus as early as day 3 of life, 9 are characterized by a memory phenotype; low proliferative capacity and interleukin-2 (IL-2) production; secretion of high levels of the immunosuppressive cytokines IL-10 and TGF-␤; and expression of cytotoxic Tlymphocyte antigen 4 (CTLA-4), 10-13 a molecule that contributes to orally induced tolerance. 14 These cells have been described in a variety of experimental models to protect from autoimmune diseases, as well as colitis and allograft rejection. 8 Reminiscent to these cells, IL-10-producing ovalbumin (OVA)-specific CD4 ϩ T clones (Tr1) generated in vitro after repeated stimulation with antigen in the presence of IL-10 were shown to prevent colitis when cotransferred with naive CD4 ϩ CD45RB high T cells in OVAfed immunocompromised severe combine immunodeficiency (SCID) or Nude mice. 15 Interestingly, mice genetically deficient for either IL-2, IL-2R, T-cell receptor ␣␤ (TcR␣␤), TGF␤, IL-10, or major histocompatibility complex (MHC) class II were shown to develop spontaneous colitis, [16][17][18][19][20] compatible with a shared physical or functional defect in the regulatory CD4 ϩ CD25 ϩ subset. Although recent studies in TcR transgenic models have reported that oral antigen delivery can induce activation and/or differentiation of regulatory CD4 ϩ CD25 ϩ T cells, 21,22 evidence that they are instrumental for in vivo induction of oral tolerance has not been provided. Moreover, evidence as to whether CD4 ϩ CD25 ϩ cells are responsible for peripheral suppression of antigen-specific CD8 ϩ cytotoxic T-lymphocyte (CTL) responses is still sparse. 23 In this study we examined whether CD4 ϩ CD25 ϩ T cells contribute to oral tolerance in normal nonlymphopenic hosts, using a pathophysiologic model of antigen-specific skin in...

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“…In the inflammation occurring during CHS, mediators such as interferon (IFN)-γ activate inflammatory cells. 14) IFN-γ can be produced by Th1 cells, B cells, and natural killer (NK) cells. 15) IFN-γ-producing lymphocytes are attracted by a chemokine, namely, macrophage inflammatory protein (MIP)-1α.…”

Section: Introductionmentioning

confidence: 99%

17.BETA.-Estradiol Enhances Interleukin-18 mRNA Expression after Sensitization of Mice with Contact Hypersensitivity

Sakazaki

Fujiyama

Ueno

et al. 2009

JOURNAL OF HEALTH SCIENCE

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To clarify the mechanism underlying the enhancing effect of 17β-estradiol (E2) on contact hypersensitivity (CHS) and the expression of interferon (IFN)-γ in mice, the mRNA expression levels of interleukin (IL)-18 were evaluated. Female BALB/c mice aged 3 weeks were ovariectomized, administered 3.2 µg of E2, and sensitized by 50 µl of 3% 4-ethoxymethylene-2-phenyl-2-oxazolin-one (OXA). Seven days later, CHS was elicited by the application of 7.5 µl of 1% OXA on the ear auricles. The auricles, cervical lymph nodes and spleens were excised, and gene expression was evaluated by reverse transcription-polymerase chain reaction. E2 enhanced the expression of IL-18 mRNA in the spleen on the following day and in the ear auricles on days 4 and 7 after sensitization with OXA. The preadministration of an antibody against IL-18 receptor suppressed the CHS and reduced IFN-γ mRNA expression in E2-administered mice. IL-18 was present in the dermis of the ear skin and absent in the epidermis. E2 also enhanced the expression of IFN-γ and IL-18 mRNAs in splenocytes cultured with lipopolysaccharide (LPS). IL-18 protein was detected by flow cytometry in CD4 + , CD8 + and NKG2 + lymphocytes among splenocytes cultured with LPS. These results suggest that E2 enhances lymphocyte activation in the sensitization phase of CHS, and that IFN-γ mRNA expression is enhanced in the elicitation phase of CHS.

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Oral Administration of Hapten Inhibits In Vivo Induction of Specific Cytotoxic CD8+ T Cells Mediating Tissue Inflammation: A Role for Regulatory CD4+ T Cells

Cited by 54 publications

References 35 publications

B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance

B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance

Innate CD4+CD25+ regulatory T cells are required for oral tolerance and inhibition of CD8+ T cells mediating skin inflammation

17.BETA.-Estradiol Enhances Interleukin-18 mRNA Expression after Sensitization of Mice with Contact Hypersensitivity

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