Antigen presenting cell‐derived IL‐6 restricts Th2‐cell differentiation

The identification of DC‐derived signals orchestrating activation of Th1 and Th17 immune responses has advanced our understanding on how these inflammatory responses develop. However, whether specific signals delivered by DCs also participate in the regulation of Th2 immune responses remains largely unknown. In this study, we show that administration of antigen‐loaded, IL‐6‐deficient DCs to naïve mice induced an exacerbated Th2 response, characterized by the differentiation of GATA‐3‐expressing T lymphocytes secreting high levels of IL‐4, IL‐5, and IL‐13. Coinjection of wild type and IL‐6‐deficient bone marrow‐derived dendritic cells (BMDCs) confirmed that IL‐6 exerted a dominant, negative influence on Th2‐cell development. This finding was confirmed in vitro, where exogenously added IL‐6 was found to limit IL‐4‐induced Th2‐cell differentiation. iNKT cells were required for optimal Th2‐cell differentiation in vivo although their activation occurred independently of IL‐6 secretion by the BMDCs. Collectively, these observations identify IL‐6 secretion as a major, unsuspected, mechanism whereby DCs control the magnitude of Th2 immunity.     

The lectin pathway of complement: Advantage or disadvantage in HIV pathogenesis?

The pattern recognition molecules of the lectin complement pathway are important components of the innate immune system with known functions in host–virus interactions. This paper summarizes current knowledge of how these intriguing molecules, including mannose-binding lectin (MBL), Ficolin-1, -2 and -3, and collectin-11 (CL-11) may influence HIV-pathogenesis. It has been demonstrated that MBL is capable of binding and neutralizing HIV and may affect host susceptibility to HIV infection and disease progression. In addition, MBL may cause variations in the host immune response against HIV. Ficolin-1, -2 and -3 and CL-11 could have similar functions in HIV infection as the ficolins have been shown to play a role in other viral infections, and CL-11 resembles MBL and the ficolins in structure and binding capacity.     

The site of tumor development determines immunogenicity via temporal mobilization of antigen‐laden dendritic cells in draining lymph nodes

The elimination of solid tumors largely depends on effective T‐cell priming by dendritic cells (DCs). For decades, studies focusing on antitumoral immune responses have been performed with tumors transplanted subcutaneously (s.c.). These studies however do not take into account the heterogeneous tissue distribution and functionality of the different DC subsets. Given the crucial role of DCs in inducing protective immune response, we postulated that the anatomic location of tumor development may greatly impact tumor immunogenicity. We therefore implanted tumor cells either in the DC‐rich dermis environment or in the s.c. tissue that mainly contains macrophages and monocytes. We showed that intradermal (i.d.), but not s.c. tumors are rapidly rejected in a T‐cell‐dependent manner and induce protective T‐cell responses. The rejection of i.d. tumors correlates with rapid recruitment of dermal DCs presenting the tumor antigen to both CD4 and CD8 T cells in the draining lymph nodes (dLNs). The same DC subsets were mobilized upon s.c. tumor transplantation but with delayed kinetics. Altogether, our results show that the anatomical site of tumor development influences tumor immunogenicity, notably by controlling the kinetics of DC mobilization in the draining LNs.     

Plasmacytoid dendritic cells are dispensable for noninfectious intestinal IgA responses in vivo

Intestinal DCs orchestrate gut immune homeostasis by dampening proinflammatory T‐cell responses and inducing anti‐inflammatory IgA responses. Although no specific DC subset has been strictly assigned so far to govern IgA response, some candidate subsets emerge. In particular, plasmacytoid DCs (pDCs), which notoriously promote anti‐viral immunity and T‐cell tolerance to innocuous antigens (Ags), contribute to IgA induction in response to intestinal viral infection and promote T‐cell‐independent IgA responses in vitro. Here, using two transgenic mouse models, we show that neither short‐term nor long‐term pDC depletion alters IgA class switch recombination in Peyer's patches and frequency of IgA plasma cells in intestinal mucosa at steady state, even in the absence of T‐cell help. In addition, pDCs are dispensable for induction of intestinal IgA plasma cells in response to oral immunization with T‐cell‐dependent or T‐cell‐independent Ags, and are not required for proliferation and IgA switch of Ag‐specific B cells in GALT. These results show that pDCs are dispensable for noninfectious IgA responses, and suggest that various DC subsets may play redundant roles in the control of intestinal IgA responses.     

The NOD2 receptor does not play a major role in the pathogenesis of Group B Streptococcus in mice

Group B Streptococcus (GBS) capsular type III is an important agent of life-threatening invasive infections. It has been previously shown that encapsulated GBS is easily internalized by dendritic cells (DCs) and this internalization has an impact on cytokine production. The intracellular receptors or pathways underlying this response are not well understood. In this work, we investigated the role of NOD2 in the pathogenesis of GBS using a mouse model of infection. NOD2^−/− mice showed similar levels of survival and bacteremia than control mice. Interestingly, ex vivo analysis of total spleen cells from infected animals showed that the absence of NOD2 results in reduced production of inflammatory cytokines. However this abridged inflammatory response does not seem to improve mouse survival. In conclusion, we demonstrated that NOD2 is not a crucial receptor to fight GBS infection and only partially contributes to the inflammatory response.     

Leukemia derived dendritic cell (DCleu) mediated immune response goes along with reduced (leukemia-specific) regulatory T-cells

The blastmodulatory Kit-M, composed of granulocyte-macrophage colony-stimulating-factor (GM-CSF) and Prostaglandin E1 (PGE₁), is known to convert myeloid leukaemic blasts (from AML patients) into leukaemia derived dendritic cells (DC_leu), which activate immunoreactive cells to gain antileukemic/leukaemia-specific activity. In this study we had a special focus on the influence of Kit-M treated, DC/DCleu containing patients’whole blood (WB, n = 16) on the provision of immunosuppressive regulatory T-cells.We could confirm that Kit-M significantly increased frequencies of (mature) dendritic cells (DC) and DC_leu from leukemic whole blood (WB) without induction of blast proliferation. After mixed lymphocyte culture (MLC) with patients’ T-cells we confirmed that DC_leu mediated leukemia-specific responses- going along with activated and leukemia-specific T- and NK-cells in an intracellular cytokine staining assay (ICS) and a degranulation assay (Deg)- resulted in an increased anti-leukemic cytotoxicity (Cytotoxicity Fluorolysis Assay = CTX). We could demonstrate that (leukemia-specific) CD4⁺ and CD8⁺ regulatory T-cell population (T_reg) decreased significantly after MLC compared to controls. We found significant positive correlations of leukemia-specific CD3⁺CD4⁺ cells with frequencies of (mature) DC_leu. Achieved anti-leukemic cytotoxicity correlated significantly positive with leukemia-specific CD3⁺CD8⁺ cells and significantly negatively with (leukemia-specific) T_reg.In summary we demonstrate that immunesuppressive (leukemia-specific) regulatory T-cells are significantly downregulated after Kit-M triggered MLC- going along with a (reinstalled) antileukemic reactivity of the immune system (as demonstrated with functional assays ICS, Deg, CTX).     

Therapeutic potential of IL-10 and its viral homologues: an update

IL-10, initially identified as a cytokine synthesis inhibiting factor released by Type 2 T-helper (T_H2) cells, is now known to be produced by many cell populations and to play a central role in the regulation of immune and inflammatory responses. Although its principal function is to limit, and ultimately terminate, inflammatory responses by suppressing the activation and effector function of T cells, monocytes and macrophages, IL-10 also affects the growth and/or differentiation of B cells, natural killer cells, cytotoxic and T_H2 cells, mast cells and dendritic cells. Importantly, IL-10 appears to be essential for the development and function of a subset of regulatory T cells prominently involved in the maintenance of peripheral tolerance and the control of immune homeostasis. IL-10 exerts these various effects by binding to a cellular receptor (IL10R) composed of at least two subunits. Furthermore, several viral IL-10 homologues that signal through the same receptor complex display immunosuppressive activities similar to those of the mammalian cytokine. Preclinical studies have suggested that the immunosuppressive activities of IL-10 hold potential for the treatment of inflammatory and autoimmune disorders. Recombinant human IL-10 (ilodecakin, Tenovil^TM, Schering-Plough) has therefore been developed and evaluated by systemic administration in a number of such diseases, including Crohn’s disease, rheumatoid arthritis, psoriasis, chronic hepatitis C and acute pancreatitis. Although the results of these clinical trials have been heterogeneous and disappointing overall, they have provided further insight into the immunobiology of IL-10 and have suggested possible approaches to improve its therapeutic utility. Here, the patent literature associated with IL-10 and its viral homologues is discussed in the light of these recent advances, taking into perspective the experimental evidence that supports future prospects for the therapeutic use of this important class of immunoregulatory cytokines.     

Murine CD8(+)T cell cytotoxicity against schistosomula induced by inoculation of schistosomal 22.6/26GST coupled Sepharose 4B beads

Schistosomasis is a world-wide parasitic disease. Although chemotherapy is the main treatment method for schistosomasis currently, it cannot prevent schistosome reinfection. Up to now no effective vaccine is available to prevent schistosomiasis. Dendritic cells (DCs) are one of the key players in the cellular immune response and play an important role in antigen presentation as antigen-presenting cells. Here we reported a novel large particulate antigen, in which Sepharose 4B beads were coated with Sj22.6/26GST. Our results showed that this particulate antigen could be cross-presented by DCs to CD8(+)T cells. Furthermore, CD8(+)T cells stimulated by particulate antigen directly exerted cytotoxicity against Schistosoma japonicum schistosomula. We also demonstrated that S. japonicum schistosomula acquired the MHC class I molecules from host blood serum and presented the molecules at the larval surface. While it may help them escape from the host immune surveillance, these MHC I-antigen complexes presented on the surface render schistosomula the potential targets of the CD8(+)T cell cytotoxicity induced by particulate antigen-based vaccine. Finally we evaluated the protective immunity of this particulate vaccine in a mouse infection challenge model. Our data clearly showed that the particulate vaccine induced a partial reduction in both worm burdens and egg loads. Taken together, these results suggest that this large particulate vaccine could be a potential vaccine for the prevention of schistosome infection.     

Adjuvant-active aqueous extracts from Artemisia rupestris L. improve immune responses through TLR4 signaling pathway

Activating innate immunity by an adjuvant is required in vaccine development. The study aims to investigate adjuvant effects of aqueous extracts of Artemisia rupestris L. (AEAR) in vivo and in vitro. ICR mice were subcutaneously administered with antigen and AEAR at various doses to evaluate their immune responses of antibodies, dendritic cells (DCs), regulatory T cells (Treg), splenic lymphocyte, and cytokine. The evaluation results showed that AEAR could largely increase titers of antigen-specific antibodies (IgG, IgG₁, and IgG_2a) and T cell proliferation. AEAR also increased expression of IFN-γ in CD8⁺T cells as well as IL-4 and INF-γ expression in CD4⁺T cells. Expression levels of MHC-II, CD40, CD80, and CD86 on DCs were significantly elevated, whereas the Treg frequency was significantly decreased. AEAR (200 μg) showed remarkable adjuvant activity. Furthermore, AEAR enhanced MHC-II, CD40, CD80, and CD86 expression as well as the yields of TNF-α and IL-12 on DCs through toll-like receptor4 (TLR4) in vitro. Those results indicated that AEAR could serve as an efficacious immune stimulator for vaccines because it significantly enhanced specific immune responses by promoting DCs maturation and reduced Treg through TLR4 signaling pathway.