Interleukin-18 synthesis and secretion by dendritic cells are modulated by interaction with antigen-specific T cells (original) (raw)
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Iranian journal of allergy, asthma, and immunology, 2007
Predominantly antibody deficiencies are a category of primary immunodeficiency diseases, which consist of several rare disorders such as common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA). We evaluated the effects of CVID and XLA patients' sera as a source of microenviromental factors on maturation and function of monocyte-derived DCs. Blood was collected from 10 CVID and 5 XLA patients before immunoglobulin replacement therapy and also from 8 healthy volunteers in order to obtain necessary sera for this study. Monocyte derived DCs were generated from blood cells obtained from healthy volunteers in the presence of GM-CSF, IL-4 and 10% serum concentrations from cases and controls. Immature DCs were incubated with monocyte conditioned medium (MCM) and TNF- in order to generate mature DCs. Interleukin 18 (IL-18) production by CD40L-activated mature DCs was measured after 24 hours of culture in vitro.IL-18 production by DCs generated in the presence of CVI...
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s: Dendritic cells (DCs) are the most potent professional antigen presenting cells and they arise from both the myeloid and lymphoid lineages. The review is made to overview the role of dendritic cells in controlling immunity. Dendritic cells in the periphery capture and process antigens, express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerate T cells to antigens that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Tissue dendritic cells phenotypes that do have a function in primary defense will be activated to mature after encountering and ingesting of antigens. Up on activation they express major histocompatebility complex and co-stimulatory molecules, secrete different cytokines and migrate to the secondary lymphoid organ for initiation of adaptive immune response. The dendritic cells play a central role in control and regulat...
Regulation of T cell cytokine production by dendritic cells
Immunology and Cell Biology, 2000
Previous work has established that the dendritic cells (DC) of mouse spleen regulate the IL-2 production, and hence the extent of proliferation, of the CD8 T cells they activate. It is now reported here that interaction of primary CD8 T cells with splenic CD8α -DC induced much higher production of IL-3, IFN-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF), as well as IL-2, than did interaction with CD8α + splenic DC. Furthermore, the CD8α -DC also induced higher levels of IL-2, IL-3 and IL-10 production in primary CD4 T cells, compared with that induced by CD8α + DC. These quantitative differences did not involve qualitative shifts in the type of cytokine produced. Interleukin-4 production remained low in all the primary T cell cultures and restimulation experiments in secondary cultures did not reveal any bias in the cytokine production profile. When exogenous IL-2 was added to the primary cultures to ensure equal proliferation in response to CD8αor CD8α + DC, the higher level of production of IL-3, IFN-γ and GM-CSF induced by CD8α -DC was maintained. Thus, this general control of T cell cytokine production by splenic DC involves factors additional to those that govern activation of T cells into cell cycle.
…, 2001
Although it is known that dendritic cells (DCs) produce cytokines, there is little information about how cytokine synthesis is regulated during DC development. A range of cytokine mRNA/proteins was analyzed in immature (CD86 ؊) or mature (CD86 ؉) murine bone marrow (BM)derived DCs. Highly purified, flow-sorted, immature DCs exhibited higher amounts of interleukin-1␣ (IL-1␣), IL-1, tumor necrosis factor-␣ (TNF-␣), transforming growth factor 1 (TGF-1), and macrophage migration inhibitory factor (MIF) mRNA/protein than mature DCs. After differentiation, DC up-regulated the levels of IL-6 and IL-15 mRNA/protein and synthesized de novo mRNA/protein for IL-12p35, IL-12p40, and IL-18. Although immature BM-derived DCs did not stimulate naive allogeneic T cells, mature DCs elicited a mixed population of T helper (Th) 1 (mainly) and Th2 cells in 3d-mixed leukocyte reactions. CD86 ؉ BM DCs switched to different cytokine patterns according to whether they were terminally differentiated by lipopolysaccharide (LPS) or CD40 ligation. Although both stimuli increased IL-6, IL-12p40, IL-15, and TNF-␣ mRNA/ protein levels, only LPS up-regulated transcription of IL-1␣, IL-1, IL-12p35, and MIF genes. Although LPS and CD40 crosslinking increased the T-cell allostimulatory function of BM DCs, only LPS stimulation shifted the balance of naive Th differentiation to Th1 cells, a mechanism dependent on the up-regulation of IL-12p35 and not of IL-23. These results demonstrate that, depending on the stimuli used to terminally mature BM DCs, DCs synthesize a different pattern of cytokines and exhibit distinct Th cell-driving potential.
Proceedings of the National Academy of Sciences, 2002
T lymphocytes are defective in cystine uptake and thus require exogenous thiols for activation and function. Here we show that monocyte-derived human dendritic cells (DCs) release cysteine in the extracellular space. Cysteine generation is increased by lipopolysaccharide and tumor necrosis factor α, and by contact with T cells specifically recognizing soluble or alloantigens. These stimuli also induce thioredoxin (TRX) accumulation in DCs. However, only the contact with antigen-specific T cells triggers TRX secretion by the antigen-presenting cells. Fewer extracellular thiols are recovered after DC–T cell interactions when cystine uptake or TRX activity are inhibited. In addition, glutamate (Glu) and anti-TRX-inactivating antibodies inhibit antigen-dependent T lymphocyte proliferation. These findings indicate that, during antigen presentation, DCs uptake cystine and release cysteine and TRX, thus providing a reducing microenvironment that facilitates immune response.
European Journal of Immunology, 1998
IL-18 is a recently described cytokine that shares biological activities with IL-12 in driving the development of Th1-type T cells. As dendritic cells (DC) are very potent inducers of T cell proliferation and differentiation we wondered whether they utilize IL-18 as a factor driving Th1 development. We demonstrate by Northern blot and reverse transcription-PCR that various subtypes of human and murine DC as well as the DC-line XS contain IL-18 mRNA. When supernatants of either enriched Langerhans cells (LC) or bone marrow-derived DC were analyzed for production of IL-18 protein, IL-18 production was detected in an IL-18specific ELISA. To assess whether the IL-18 protein released by DC is functional, we performed a sensitive bioassay using the IL-18-dependent stimulation of concanavalin Astimulated T cells. Both, supernatants from bone marrow-derived DC and enriched LC induced IFN-+ production in the T cells. This production was partially inhibitable by addition of anti-IL-18 antiserum. In a TCR-transgenic mouse system we further demonstrate that DCderived IL-18 potentiates IL-12-dependent Th1 development. Using DC derived from IL-12 knockout animals, we show that DC-derived IL-18 by itself is not capable of inducing Th1 cell differentiation. Together the data demonstrate that subtypes of DC are able to release functional IL-18 that is able to induce IFN-+ production and Th1 differentiation in primed T cells.
International Immunology, 2004
We previously demonstrated that tumor necrosis factor (TNF)-a-matured CD16 ÿ and CD16 1 human monocyte-derived dendritic cells (16ÿmDC and 161mDC) differentially stimulate naive CD4 1 lymphocytes by inducing Th1-and Th2-like responses, respectively. Here, we further characterized the role of different DC maturation factors on Th polarization. Immature 161mDC and 16ÿmDC (iDC) obtained by culture of purified monocytes with GM-CSF and IL-4 were maturated with (i) Toll-like receptor (TLR) ligands [lipopolysaccharide (LPS)], (ii) lymphocyte-derived (soluble CD40 ligand, IFN-c) and (iii) endogenous inflammatory stimuli [TNF-a, prostaglandin (PG)E 2 ]. After activation with these stimuli, DC secrete IL-12 only in presence of LPS, and 161mDC produced lower amounts of IL-12 and IL-10 than 16ÿmDC. Allogeneic CD4 1 CD45RO ÿ lymphocytes co-cultured with 161mDC secreted higher levels of IL-4 and IL-10 than those co-cultured with 16ÿmDC, regardless of the maturation stimuli. Results were similar when DC were activated with TLR-2 or TLR-3 ligands. The higher induction of IL-4 by 161mDC was primarily dependent on IL-12, IL-4 and IL-10. IFN-c production by CD4 1 T cells was similar with all the conditions except with LPS-161mDC, which induced reduced amounts of this cytokine. Those differences were totally eliminated by neutralization of IL-12, IL-4 or IL-10. Finally, 16ÿmDC could reverse the Th2 phenotype of already committed lymphocytes toward a Th1 pattern in short-term cultures, whereas 161mDC had less ability to skew this phenotype. These results indicate that 161mDC elicit superior Th2 responses independently of the maturation factors that they received, and suggest that they could represent an important population of regulatory DC.