Faecalibacterium prausnitzii A2-165 has a high capacity to induce IL-10 in human and murine dendritic cells and modulates T cell responses

Acknowledgements This work was financially supported by the EC FP7 Cross-talk project (PITN-GA-2008-215553). The authors thank the Histology Platform from GABI research unit and especially Abdelhak Boukadiri for their technical support in the histology sample preparation and Marlène Héry, Charline Pontlevoy, Jerome Pottier and André Tiffoche (UE0907 IERP, Jouy en Josas) for their help during animal experiments. The authors thank Rafael Muñoz-Tamayo (INRA) for his help in performing the PCA.Peer reviewedPublisher PD

Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells

Sialic acids are negatively charged nine-carbon carboxylated monosaccharides that often cap glycans on glycosylated proteins and lipids. Because of their strategic location at the cell surface, sialic acids contribute to interactions that are critical for immune homeostasis via interactions with sialic acid-binding Ig-type lectins (siglecs). In particular, these interactions may be of importance in cases where sialic acids may be overexpressed, such as on certain pathogens and tumors. We now demonstrate that modification of antigens with sialic acids (Sia-antigens) regulates the generation of antigen-specific regulatory T (Treg) cells via dendritic cells (DCs). Additionally, DCs that take up Sia-antigen prevent formation of effector CD4+ and CD8+ T cells. Importantly, the regulatory properties endowed on DCs upon Sia-antigen uptake are antigen-specific: only T cells responsive to the sialylated antigen become tolerized. In vivo, injection of Sia-antigen–loaded DCs increased de novo Treg-cell numbers and dampened effector T-cell expansion and IFN-γ production. The dual tolerogenic features that Sia-antigen imposed on DCs are Siglec-E–mediated and maintained under inflammatory conditions. Moreover, loading DCs with Sia-antigens not only inhibited the function of in vitro–established Th1 and Th17 effector T cells but also significantly dampened ex vivo myelin-reactive T cells, present in the circulation of mice with experimental autoimmune encephalomyelitis. These data indicate that sialic acid-modified antigens instruct DCs in an antigen-specific tolerogenic programming, enhancing Treg cells and reducing the generation and propagation of inflammatory T cells. Our data suggest that sialylation of antigens provides an attractive way to induce antigen-specific immune tolerance

Blockade of IDO inhibits nasal tolerance induction

The amino acid tryptophan is essential for the proliferation and survival of cells. Modulation of tryptophan metabolism has been described as an important regulatory mechanism for the control of immune responses. The enzyme IDO degrades the indole moiety of tryptophan, not only depleting tryptophan but also producing immunomodulatory metabolites called kynurenines, which have apoptosis-inducing capabilities. In this study, we show that IDO is more highly expressed in nonplasmacytoid dendritic cells of the nose draining lymph nodes (LNs), which form a unique environment to induce tolerance to inhaled Ags, when compared with other peripheral LNs. Upon blockade of IDO during intranasal OVA administration, Ag-specific immune tolerance was abrogated. Analysis of Ag-specific T cells in the LNs revealed that inhibition of IDO resulted in enhanced survival at 48 h after antigenic stimulation, although this result was not mediated through alterations in apoptosis or cell proliferation. Furthermore, no differences were found in CD4(+) T cells expressing FoxP3. Our data suggest that the level of IDO expression in dendritic cells, present in nose draining LNs, allows for the generation of a sufficient number of regulatory T cells to control and balance effector T cells in such a way that immune tolerance is induced, whereas upon IDO blockade, effector T cells will outnumber regulatory T cells, leading to immunity

Fc gamma RIIB regulates nasal and oral tolerance: a role for dendritic cells

Mucosal tolerance prevents the body from eliciting productive immune responses against harmless Ags that enter the body via the mucosae, and is mediated by the induction of regulatory T cells that differentiate in the mucosa-draining lymph nodes (LN) under defined conditions of Ag presentation. In this study, we show that mice deficient in FcgammaRIIB failed to develop mucosal tolerance to OVA, and demonstrate in vitro and in vivo a critical role for this receptor in modulating the Ag-presenting capacity of dendritic cells (DC). In vitro it was shown that absence of FcgammaRIIB under tolerogenic conditions led to increased IgG-induced release of inflammatory cytokines such as MCP-1, TNF-alpha, and IL-6 by bone marrow-derived DC, and increased their expression of costimulatory molecules, resulting in an altered immunogenic T cell response associated with increased IL-2 and IFN-gamma secretion. In vivo we could show enhanced LN-DC activation and increased numbers of Ag-specific IFN-gamma-producing T cells when FcgammaRIIB(-/-) mice were treated with OVA via the nasal mucosa, inferring that DC modulation by FcgammaRIIB directed the phenotype of the T cell response. Adoptive transfer of CD4(+) T cells from the spleen of FcgammaRIIB(-/-) mice to naive acceptor mice demonstrated that OVA-responding T cells failed to differentiate into regulatory T cells, explaining the lack of tolerance in these mice. Our findings demonstrate that signaling via FcgammaRIIB on DC, initiated by local IgG in the mucosa-draining LN, down-regulates DC activation induced by nasally applied Ag, resulting in those defined conditions of Ag presentation that lead to Tr induction and tolerance

Secretory leukoprotease inhibitor in mucosal lymph node dendritic cells regulates the threshold for mucosal tolerance

The notion that the mucosal immune system maintains a tolerogenic response to harmless Ags while continually being challenged with microbial products seems an enigma. The aim of this study was to unravel mechanisms that are involved in regulating the development of tolerance under constant microbial pressure. The tolerogenic response to Ags administered via the nasal mucosa is dependent on the organized lymphoid tissue of the cervical lymph nodes (LN). We show that cervical LN differentially express secretory leukoprotease inhibitor (SLPI) compared with peripheral LN. SLPI was expressed by dendritic cells (DCs) and because SLPI is known to suppress LPS responsiveness, it was hypothesized that its expression in mucosal DCs may be required to regulate cellular activation to microbial products. Indeed, compared with wild-type controls, bone marrow-derived DCs from SLPI(-/-) mice released more inflammatory cytokines and enhanced T cell proliferation after stimulation with low dose LPS. This increased sensitivity to LPS was accompanied by increased NF-kappaB p65 activation in SLPI(-/-) DCs. In vivo, nasal application of OVA with LPS to SLPI(-/-) mice resulted in enhanced DC activation in the cervical LN reflected by increased costimulatory molecule expression and release of inflammatory cytokines. This led to failure to maintain tolerance to nasal OVA application in the presence of low doses of LPS. We propose that expression of SLPI functions as a rheostat by controlling the level of bacterial stimuli that induce mucosal DC activation. As such, it regulates the quality of the ensuing Ag-specific immune response in the mucosa draining LN