Interleukin-7 (IL-7), a product of stromal cells, provides critical signals to lymphoid cells at early stages in their development. Two types of cellular responses to IL-7 have been identified in ...lymphoid progenitors: (1) a trophic effect and (2) an effect supporting V(D)J recombination. The IL-7 receptor is comprised of two chains, IL-7R
α and
γ
c. Following receptor crosslinking, rapid activation of several classes of kinases occurs, including members of the Janus and Src families and PI3-kinase. A number of transcription factors are subsequently activated including STATs, c-
myc, NFAT and AP-1. However, it remains to be determined which, if any, previously identified pathway leads to the trophic or V(D)J endpoints. The trophic response to IL-7 involves protecting lymphoid progenitors from a death process that resembles apoptosis. This protection is partly mediated by IL-7 induction of Bcl-2, however other IL-7-induced events are probably also involved in the trophic response. The V(D)J response to IL-7 is partly mediated through increased production of Rag proteins (which cleave the target locus) and partly by increasing the accessibility of a target locus to cleavage through chromatin remodeling.
The demand for controlling T cell responses via dendritic cell (DC) vaccines initiated a quest for reliable and feasible DC modulatory strategies that would facilitate cytotoxicity against tumors or ...tolerance in autoimmunity. We studied endogenous mechanisms in developing monocyte-derived DCs (MoDCs) that can induce inflammatory or suppressor programs during differentiation, and we identified a powerful autocrine pathway that, in a cell concentration-dependent manner, strongly interferes with inflammatory DC differentiation. MoDCs developing at low cell culture density have superior ability to produce inflammatory cytokines, to induce Th1 polarization, and to migrate toward the lymphoid tissue chemokine CCL19. On the contrary, MoDCs originated from dense cultures produce IL-10 but no inflammatory cytokines upon activation. DCs from high-density cultures maintained more differentiation plasticity and can develop to osteoclasts. The cell concentration-dependent pathway was independent of peroxisome proliferator-activated receptor γ (PPARγ), a known endogenous regulator of MoDC differentiation. Instead, it acted through lactic acid, which accumulated in dense cultures and induced an early and long-lasting reprogramming of MoDC differentiation. Our results suggest that the lactic acid-mediated inhibitory pathway could be efficiently manipulated in developing MoDCs to influence the immunogenicity of DC vaccines.
Pollen-derived ROS may contribute to local innate immunity by triggering proinflammatory cytokine production of DCs. ...pollen-produced ROS affect the maturation program of DCs, hence they ...participate in the initiation of allergen-dependent adaptive immune responses.
The aim of this study was to characterize and identify the mode of action of IC31®, a two-component vaccine adjuvant. We found that IC31® was accumulated in human peripheral blood monocytes, MHC ...class II positive cells and monocyte-derived DCs (moDCs) but not in plasmacytoid DCs (pDCs). In the presence of IC31® the differentiation of inflammatory CD1a(+) moDCs and the secretion of chemokines, TNF-α and IL-6 cytokines was inhibited but the production of IFNβ was increased. Sustained addition of IC31® to differentiating moDCs interfered with IκBα phosphorylation, while the level of phospho-IRF3 increased. We also showed that both IC31® and its KLK component exhibited a booster effect on type I IFN responses induced by the specific ligands of TLR3 or TLR7/8, whereas TLR9 ligand induces type I IFN production only in the presence of IC31® or ODN1. Furthermore, long term incubation of moDCs with IC31® caused significantly higher expression of IRF and IFN genes than a single 24 hr treatment. The adjuvant activity of IC31® on the IFN response was shown to be exerted through TLRs residing in the vesicular compartment of moDCs. Based on these results IC31® was identified as a moDC modulatory adjuvant that sets the balance of the NF-κB and IRF3 mediated signaling pathways to the production of IFNβ. Thus IC31® is emerging as a potent adjuvant to increase immune responses against intracellular pathogens and cancer in future vaccination strategies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Keratinocytes have the ability to kill pathogenic fungi and bacteria by producing antimicrobial substances. Recent studies suggest that microbial components use signaling molecules of the human ...Toll‐like receptor (TLR) family to transduce signals in various cells. Here we provide evidence that keratinocytes express both TLR2 and TLR4 at the mRNA and protein levels, and show that TLR2 and TLR4 are present in the normal human epidermis in vivo and that their expression is regulated by microbial components. The expression of myeloid differentiation protein gene (MyD88), which is involved in the signaling pathway of many TLR, was also demonstrated in keratinocytes. LPS + IFN‐γ increased the expression of TLR2 and TLR4 50‐ and 5‐fold respectively. Treatment of keratinocytes with Candida albicans, mannan, Mycobacterium tuberculosis or LPS with IFN‐γ resulted in the activation and nuclear translocation of NF‐κB. Inhibition of NF‐κB blocked the Candida‐killing activity of keratinocytes, suggesting that the antimicrobial effect of keratinocytes requires NF‐κB activation. LPS + IFN‐γ, C. albicans (4 Candida/KC), peptidoglycan (1 µg/ml) or M. tuberculosis extract significantly increased IL‐8 gene expression after 3 h of treatment (P < 0.05). The increases over the 0‐h level were 15‐, 8‐, 10.8‐ and 7‐fold, respectively. The microbial compound‐induced increase in IL‐8 gene expression could be inhibited by anti‐TLR2 and anti‐TLR4 neutralizing antibodies, suggesting that TLRs are involved in the pathogen‐induced expression of this pro‐inflammatory cytokine. Our findings stress the importance of the role of keratinocytes as a component of innate immunity.
Little is known of the transcriptional events controlling the differentiation and function of dendritic cells (DC). We found that the ligand-activated transcription factor Peroxisome Proliferator ...Activated Receptor γ (PPARγ) is immediately upregulated after the induction of monocyte-derived DC differentiation. Activation of PPARγ changed the expression pattern of cell surface receptors and enhanced the internalizing activity of DC. Unexpectedly, we found that CD1 glycoproteins, a class of molecules responsible for the presentation of self and foreign modified lipids, were coordinately regulated by PPARγ activation. CD1a levels were reduced, while CD1d expression was induced. Enhanced expression of CD1d was coupled to the selective induction of invariant natural-killer T cell (iNKT cell) proliferation in the presence of α-GalCer. These results suggest that PPARγ orchestrates a transcriptional response leading to the development of a DC subtype with increased internalizing capacity, efficient lipid presentation, and the augmented potential to activate iNKT cells.
We performed clinical, immunological and genetic studies of 12 hyper-IgE syndrome (HIES) patients from 4 Hungarian, 2 Lebanese, one Russian, one Polish, and one Swedish families with autosomal ...dominant (AD) or sporadic forms of the disease to reveal cross-ethnicity of recurrent and novel mutations in the signal transducer and activator of transcription-3 gene (
STAT3). Four patients from 3 Hungarian families, and one Russian, and one Swedish patient carried the heterozygous R382W germline mutation at the DNA-binding site of STAT3. The recurrent V637M mutation affecting the SRC homology 2 (SH2) domain was detected in one Lebanese and one Polish family, and the V463del deletion located in the DNA-binding domain was unveiled in another Lebanese family. A novel H332Y mutation affecting the DNA-binding site of STAT3 in three Hungarian patients from a Gypsy family was also found. The segregation of this mutation with HIES, restriction fragment length polymorphism analysis of
STAT3 from patients and controls and the negligible production upon IL-6 stimulation of monocyte chemotactic protein-1 by the patient's blood mononuclear cells suggested that the H332Y mutation was disease-causing. These data suggest, that dominant negative mutations of the DNA-binding and SH2 domains of STAT3 cause AD and sporadic cases of HIES in different ethnic groups with R382W as the predominant mutation found in 5 of the 9 families. Functional and genetic data support that the novel H332Y mutation may result in the loss of function of STAT3 and leads to the HIES phenotype.
Tissue transglutaminase (TGase2) is a protein-crosslinking enzyme known to be associated with the in vivo apoptosis program. Here we report that apoptosis could be induced in TGase2-/-mice; however, ...the clearance of apoptotic cells was defective during the involution of thymus elicited by dexamethasone, anti-CD3 antibody, or γ-irradiation, and in the liver after induced hyperplasia. The lack of TGase2 prevented the production of active transforming growth$factor\!-\!\beta1$in macrophages exposed to apoptotic cells, which is required for the up-regulation of TGase2 in the thymus in vivo, for accelerating deletion of CD4+CD8+ cells and for efficient phagocytosis of apoptotic bodies. The deficiency is associated with the development of splenomegaly, autoantibodies, and immune complex glomerulonephritis in TGase2-/-mice. These findings have broad implications not only for diseases linked to inflammation and autoimmunity but also for understanding the interrelationship between the apoptosis and phagocytosis process.
In this study the alteration of endothelial function, arterial stiffness and autoantibodies was investigated in patients with UCTD.
Thirty-one patients with UCTD were included in this prospective ...study. All the patients remained in the UCTD stage during the average 3.8 years follow-up period. The onset of UCTD was denoted as UCTD1, while the end of the follow-up period was called UCTD2. Flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT), autoantibodies such as anti-SSA, anti-SSB, anti-DNA, anti-RNP, anti-CCP, aCL, anti-oxidized low-density lipoprotein (oxLDL) and AECA, von Willebrand factor antigen, thrombomodulin (TM), endothelin 1 (ET-1) and lipid parameters were measured.
In the UCTD1 stage, high-sensitivity CRP (hsCRP) and endothelial cell activation and/or damage markers such as TM, ET-1 and AECA levels were significantly higher compared with controls (controls vs UCTD1: hsCRP, P < 0.0001; TM, P = 0.001; ET-1, P < 0.0001). In the UCTD2 stage, the carotid IMT increased (UCTD1 vs UCTD2, P = 0.01) and FMD further deteriorated (UCTD1 and UCTD2, P = 0.001). In UCTD2 there was a close correlation between the carotid IMT, and duration of the disease (r = 0.612, P < 0.001), the level of TM (r = 0.673, P < 0.001) and anti-oxLDL (r = 0.800, P < 0.001).
Our data suggest that the presence of inflammation and autoantibodies provoke endothelial cell activation and/or injury in UCTD patients. The persistent endothelial dysfunction may provoke the development of atherosclerosis. FMD was found to be the most sensitive marker for arterial stiffness, and the increase of IMT clearly indicated the existence of preclinical atherosclerosis in UCTD patients.
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