CD4+CD25+ T regulatory cells induced by LPS-activated bone marrow dendritic cells suppress experimental autoimmune uveoretinitis in vivo

Siepmann, Kirsten; Biester, Sabine; Plskova, Jarka; Muckersie, Elizabeth; Duncan, Linda; Forrester, John V.

doi:10.1007/s00417-006-0356-9

Cited by 29 publications

(24 citation statements)

References 39 publications

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“…Additionally, the cells induced by CD40-B have greater suppressive capacity than those induced by imDCs. Similar to previous reports that cell-cell contact is required for the induction of CD4 1 Tregs by imDCs or plasmacytoid DCs, 27,28 we Figure 5 Generation of CD4 high CD25 1 Tregs is partially dependent on HLA-DR and CD80/86 expression. Naive CD4 1 CD25 2 T cells isolated from normal PBMCs were cocultured with allogeneic CD40-B (a) or imDCs (b) at a T/B or T/ DC ratio of 10/1 in the presence of neutralizing mAbs against HLA-DR, CD80/ CD86 or relevant isotype control for 9 days.…”

Section: Discussionsupporting

confidence: 87%

CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD4+ regulatory T cells

et al. 2010

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CD4 1 regulatory T cells (Tregs) play an important role in maintaining immune tolerance by suppressing pathologic immune responses. The generation of large numbers of antigen-specific Tregs ex vivo is critical for the development of clinical immunotherapy based on the adoptive transfer of Tregs. Both CD40-activated B cells (CD40-B) and immature dendritic cells (imDCs) have been used as professional antigen-presenting cells (APCs) to generate antigen-specific Tregs. However, the efficiencies of CD40-B and imDCs to generate CD4 1 Tregs have not been compared directly and the mechanism driving the generation of these Tregs remains largely unknown. In this study, we found that CD40-B exhibited mature phenotypes and were more able to induce and expand CD4 high CD25 1 Tregs than imDCs. Moreover, Tregs induced by CD40-B had greater suppressive capacity than those induced by imDCs. The generation of CD4 high CD25 1 Tregs by CD40-B and imDCs is cell-cell contact dependent and partially relies on the expression of human leukocyte antigen (HLA)-DR and CD80/86. Differences in CD4 high CD25 1 Treg generation efficiency were largely explained by the production of endogenous IL-2 by CD40-B. Our results suggest that CD40-B is better able to generate large numbers of antigen-specific Tregs than imDCs. Additionally, using CD40-B to generate Tregs may accelerate the clinical use of Treg-based immunotherapy in the treatment of allograft rejection, graft versus host disease (GVHD) and autoimmune diseases.

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Section: Discussionsupporting

confidence: 87%

CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD4+ regulatory T cells

et al. 2010

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“…We have previously demonstrated that LPS-activated BMDC secrete a different set of cytokines by varying the timing of LPS activation of freshly purified immature DC from B10RIII (H2 k ) mice (17,23). In this study, we confirm this result in C57BL/6 (H2 b ) mice: freshly purified BMDC are CD11C ϩlow CD11b ϩ CD4 Ϫ CD8a Ϫ expressing low levels of CD40, MHCII, and CD86 ( Fig.…”

Section: Differential Cytokine Secretion By Bone Marrow-derived DC (Bsupporting

confidence: 82%

“…Mature DC have in certain strains and protocols either induced or exacerbated autoimmune inflammation (2, 10 -16), whereas in other circumstances mature, immature, and semimature DC have inhibited disease (3,4,(17)(18)(19)(20)(21)(22). In addition, the cytokine profile of the DC (either IL-10 or IL-12 producing) seemed to affect the tolerizing effect of DC in certain models (23). In several models, administration of DC appears to lead to expansion of Tregs, whereas under other circumstances, they appear to suppress autoimmunity by shifting the Th1 cell profile toward the Th2 phenotype (18,24).…”

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confidence: 99%

Lipopolysaccharide-Activated IL-10-Secreting Dendritic Cells Suppress Experimental Autoimmune Uveoretinitis by MHCII-Dependent Activation of CD62L-Expressing Regulatory T Cells

Lau

Biester

Cornall

et al. 2008

The Journal of Immunology

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Dendritic cells (DC) are key regulators of immune responses. Mature DC are traditionally considered to be immunogenic, although there is accumulating evidence that they can also be tolerogenic and induce Ag-specific regulatory T cells (Tregs). However, the mechanism of this Treg induction and the site of Treg action in vivo are yet to be defined. In this study, using the experimental model of interphotoreceptor retinoid-binding protein peptide (1–20)-induced experimental autoimmune uveoretinitis, we show that s.c. inoculation of IRBP-peptide-pulsed IL-10-producing LPS-activated mature DC (IL-10-DC) at one site (the cervical region) suppresses autoimmunity induced at a separate site (the inguinal region). Our data show that s.c. IL-10-DC correlates with an increase in the number of CD4+CD25+Foxp3+ Tregs at the DC-draining lymph nodes (DC-dLN). However, although MHCII−/− IL-10-DC also induces Treg expansion at this DC-dLN, they failed to suppress experimental autoimmune uveoretinitis. Furthermore, unlike wild-type IL-10-DC, MHCII−/− IL-10-DC did not correlate with an increase in the percentage of Tregs expressing CD62L at the DC-dLN, nor did they associate with an increase in Treg number at a distal site. Similar effects were also observed after s.c. hen egg lysozyme-pulsed IL-10-DC, which produced a strong reduction in the number and activation of proliferating Ag-specific CD4+ 3A9 T effector cells. We therefore propose that IL-10-DC require MHCII-dependent Ag presentation, and hence TCR ligation, to promote CD62L-mediated trafficking of Tregs to the site of T effector cell priming, where they suppress autoimmunity.

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“…Our previous data15, 42 showing that s.c. administration of LPS‐primed BMDC induces expansion of regulatory T cells at the skin‐draining lymph nodes, suggest that CD4 + regulatory T cells are likely to contribute toward the observed tolerogenic effect. Induction of regulatory T cells by LPS‐primed ET‐DC is probably a consequence of modified cell signalling induced in the DC by high‐dose LPS, which includes reduced signalling through NF‐ κ B (see also Fig.…”

Section: Discussionmentioning

confidence: 94%

“…We have previously shown that LPS‐primed bone‐marrow‐derived DC (BMDC), inoculated subcutaneously (s.c.) as a single injection, suppressed experimental autoimmune uveoretinitis (EAU) in the C57BL/6 mouse, induced using interphotoreceptor retinoid‐binding protein (IRBP) peptide emulsified in complete Freund's adjuvant (CFA) containing Mycobacterium tuberculosis 15, 42. However, in our previous work the LPS extract contained small amounts of other TLR 15, 43, 44.…”

Section: Introductionmentioning

confidence: 94%

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

et al. 2016

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SummaryExposure of bone‐marrow‐derived dendritic cells (BMDC) to high‐dose ultrapure lipopolysaccharide for 24 hr (LPS‐primed BMDC) enhances their potency in preventing inter‐photoreceptor retinoid binding protein: complete Freund's adjuvant‐induced experimental autoimmune uveoretinitis (EAU). LPS‐primed BMDC are refractory to further exposure to LPS (= endotoxin tolerance), evidenced here by decreased phosphorylation of TANK‐binding kinase 1, interferon regulatory factor 3 (IRF3), c‐Jun N‐terminal kinase and p38 mitogen‐activated protein kinase as well as impaired nuclear translocation of nuclear factor κB (NF‐κB) and IRF3, resulting in reduced tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), IL‐12 and interferon‐β secretion. LPS‐primed BMDC also show reduced surface expression of Toll‐like receptor‐4 and up‐regulation of CD14, followed by increased apoptosis, mediated via nuclear factor of activated T cells (NFATc)‐2 signalling. LPS‐primed BMDC are not only homotolerant to LPS but are heterotolerant to alternative pathogen‐associated molecular pattern ligands, such as mycobacterial protein extract (Mycobacterium tuberculosis). Specifically, while M. tuberculosis protein extract induces secretion of IL‐1β, TNF‐α and IL‐6 in unprimed BMDC, LPS‐primed BMDC fail to secrete these cytokines in response to M. tuberculosis. We propose that LPS priming of BMDC, by exposure to high doses of LPS for 24 hr, stabilizes their tolerogenicity rather than promoting immunogenicity, and does so by multiple mechanisms, namely (i) generation of tolerogenic apoptotic BMDC through CD14:NFATc signalling; (ii) reduction of NF‐κB and IRF3 signalling and downstream pro‐inflammatory cytokine production; and (iii) blockade of inflammasome activation.

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CD4+CD25+ T regulatory cells induced by LPS-activated bone marrow dendritic cells suppress experimental autoimmune uveoretinitis in vivo

Cited by 29 publications

References 39 publications

CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD4+ regulatory T cells

CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD4+ regulatory T cells

Lipopolysaccharide-Activated IL-10-Secreting Dendritic Cells Suppress Experimental Autoimmune Uveoretinitis by MHCII-Dependent Activation of CD62L-Expressing Regulatory T Cells

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

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