scholarly journals Dendritic-cell-associated C-type lectin 2 (DCAL-2) alters dendritic-cell maturation and cytokine production

Blood ◽  
2006 ◽  
Vol 107 (4) ◽  
pp. 1459-1467 ◽  
Author(s):  
Chang-Hung Chen ◽  
Helen Floyd ◽  
N. Eric Olson ◽  
Dario Magaletti ◽  
Chang Li ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cell ◽  
Cytokine Production ◽  
Dendritic Cell Maturation ◽  
Receptor Internalization ◽  
Th1 Cells ◽  
Dc Functions ◽  
Lectin Receptors ◽  
Ifn Γ ◽  
Dc Maturation

Dendritic-cell (DC)-associated C-type lectin receptors (CLRs) take up antigens to present to T cells and regulate DC functions. DCAL-2 is a CLR with a cytosolic immunoreceptor tyrosine-based inhibitory motif (ITIM), which is restricted to immature DCs (iDCs), monocytes, and CD1a+ DCs. Cross-linking DCAL-2 on iDCs induced protein tyrosine phosphorylation and MAPK activation as well as receptor internalization. To test if DCAL-2 is involved in DC maturation and cytokine expression, we stimulated iDCs with anti-DCAL-2 mAb with or without LPS, zymosan, or CD40L. While anti-DCAL-2 did not induce iDCs to mature, it did up-regulate CCR7 expression and IL-6 and IL-10 production. DCAL-2 signals augmented DC maturation induced by LPS or zymosan, increasing both CCR7 and DC-LAMP expression. Of interest, DCAL-2 ligation had the opposite effects on TLR versus CD40L signaling: anti-DCAL-2 suppressed TLR-induced IL-12 expression, but significantly enhanced CD40L-induced IL-12 production. DCAL-2 ligation also suppressed the ability of TLR-matured DCs to induce IFN-γ-secreting Th1 cells but augmented the capacity of CD40L-matured DCs to polarize naive T cells into Th1 cells. Thus, DCAL-2 may program DCs differently depending on whether DCs are signaled via TLRs or by T cells. DCAL-2 may be a potential immunotherapeutic target for modulating autoimmune diseases or for developing vaccines.

scholarly journals Infusion of Ex Vivo Activated Donor Type 2 Innate Lymphoid Cells Inhibit Th1 Activity and Reduces Acute Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 538-538
Author(s):  
Danny Bruce ◽  
Michelle West ◽  
Trisha A Dant ◽  
Angela Panoskaltsis-Mortari ◽  
Bruce R. Blazar ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Cytokine Production ◽  
Lymphoid Cells ◽  
Th1 Cells ◽  
Gi Tract ◽  
Donor T Cells ◽  
Conditioning Therapy ◽  
Ifn Γ

Abstract The particular subsets of T cells that mediates aGvHD is not clear. Several studies have implicated Th1 and/or Th17 T cells in the pathogenesis of aGvHD. Pre-clinical data suggest that IFN-γ producing Th1 cells are perhaps more important for GI tract aGvHD whereas IL-17 producing Th17 cells are more important for skin and lung pathology. However, both murine models and clinical data indicate that suppression of Th1 and Th17 responses by shifting to a Th2 T cell phenotype limits aGvHD. One potential mechanism for the enhanced Th1 tropism of the lower GI tract is the role of conditioning therapy on the release of cytokines and bacterial products that may polarize naïve T cells toward Th1 cells. The explosion of data surrounding innate immune cells, such as type 2 innate lymphoid cells (ILC2) has increased the possibility of discovering additional candidate suppressive cells. In patients undergoing allo-HCT, peripheral blood ILCs slowly recover and activated ILCs are associated with reduced GVHD lethality. Since ILC2 cells may drive donor Th2 responses that reduce GVHD lethality and hence their deficiency may predispose to Th1 mediated GVHD, we quantified ILC2 numbers in the GI tract and secondary lymphoid organs after radiation. B6D2 mice were given a lethal dose of radiation and ILCs enumerated using flow cytometry. As shown by others, ILC3 cells in the lamina propria (LP) of the colon are resistant to radiation but CD4+ T cells in the LP, spleen and MLN are sensitive to radiation showing significant reduction of total cells within 24 hrs. In striking contrast to ILC3 cells, ILC2 cells from the LP of the colon and spleen were highly sensitivite to radiation. Thus, the absence of recipient ILC2 cells in the colon and MLN, may critically lead to alterations in the microenvironment leading to Th1 polarization in the lower GI tract induced after allo-SCT. Given ILC2 production of Th2 cytokines and the data indicating that shifting the cytokine micro-environment away from Th1/Th17 to Th2 reduces the severity of aGVHD, we hypothesized that co-transplantation of ILC2 cells would reduce aGvHD and increase survival after allo-SCT. ILC2 cells can be indentified as lin- and ICOS+, CD127+ and ST2+. ILC2 cells were expanded for 6 days in the presence of IL-7 and IL-33 which resulted in increased percentages of IL-4, IL-5 and IL-13 expressing cells with no evidence of expansion of other ILC groups based upon IFN-γ expression for ILC1 or IL-22 expression for ILC3 cells. To test the efficacy of restoring ILC2 cells after radiation, we performed survival studies in two distinct aGVHD models. In the B6 to BALB/c models of aGvHD after allo-SCT, co-transplantation of one dose of ILC2 cells significantly improved survival after allo-SCT (p<0.0001 log rank) (Figure 1A) with an increase in median survival of 12 days and a reduction in clinical GvHD score (Day 20 score, 6.5 ± 0.3 vs. 3.5 ± 0.4 SEM), beginning at day 10 in a very stringent MHC completely mismatched model. An even greater improvement in survival was seen with ILC2 infusion at the time of transplant in B6D2F1 recipients of B6 bone marrow and T cells. In the B6 to BALB/c model, analysis of donor T cells cytokine production by flow cytometry showed a significant reduction in the frequency of IFNγ producing CD4+ T cells in the LP of recipients of ILC2 cells (Figure 1B). Interestingly, we found that ILC2 cells were equally effective in the complete mismatch model when given on the day of transplant or seven days after transplant. In summary, we have shown that ILC2 cells are radiation sensitive and that co-infusion of a single dose of ILC2 can increase survival, reduce clinical signs of aGvHD and reduced Th1 cytokine production by donor T cells. These data suggest that the Th1 skewed microenvironment in target organs of GvHD seen after conditioning therapy may be due to reduce ILC2 numbers and replacing the ILC2 population with donor-derived cells in the transplant recipient returns the immune microenvironment to a more desirable, tolerogenic status. Figure 1 Figure 1. Donor ILC2 cells limit aGvHD. (A) Lethally irradiated BALB/c mice (850cGy) received 4.0 x 106 TCD BM (BM only), BM plus 5.0 x 105 total splenic T cells (Ctrl) or BM plus T cells with 2.0 x 106 ILC2 cells (Treatment). (A) Percent survival after allo-SCT. This represents 4 independent experiments combined, n=25. (B) Percentage of IFN-γ producing donor CD4+ T cells in the LP at day 12, represents 2 experiments, n=4 each. Disclosures No relevant conflicts of interest to declare.

scholarly journals Dendritic Cells Promoted by Ginseng Saponins Drive a Potent Th1 Polarization

2008 ◽  
Vol 3 ◽  
pp. BMI.S585 ◽  
Author(s):  
Masao Takei ◽  
Eiichi Tachikawa ◽  
Akemi Umeyama
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cell Polarization ◽  
Th1 Cells ◽  
Human Monocytes ◽  
Ifn Γ ◽  
Pharmacologically Active ◽  
Dc Maturation

Dendritic cells (DC) play a pivotal role in the initiation of T-cell-mediated immune responses, making them an attractive cellular adjuvant for use in cancer vaccines. The interaction of T cells with DC is crucial for directing T cell differentiation towards the Th1, Th2 or Th17 type, and several factors determining the direction of the T cell polarization. IL-12 plays a central role in the immune system, not only by augmenting the cytotoxic activity of T cells and NK cells and regulating IFN-γ production, but also by the capacity of IL-12 to promote the development of Th1 cells. Therefore, it is important to identify factors that might affect the differentiation, maturation and function of DC. Ginseng is a medicinal herb widely used in Asian countries, and many of its pharmacological actions are attributed to the ginsenosides. Moreover, T-cadinol and calamenene are sesquterpenes isolated from the heartwood of Cryptomeria japonica being pharmacologically active substances. We investigated whether M1 and M4, end products of steroidal ginseng saponins metabolized in digestive tracts, as well as T-cadinol and calamenene can drive DC maturation from human monocytes in vitro. Human monocytes were cultured with GM-CSF and IL-4 for 6 days under standard conditions, followed by another 2 days in the presence of M1, M4, T-cadinol or calamenene. The expression levels of CD1a, CD80, CD83, CD86 and HLA-DR on M1-primed DC, M4-primed DC, T-cadinol-primed DC and calamenene-primed DC were enhanced with a concomitant decrease in endocytic activity. M1-primed DC, M4-primed DC, T-cadinol-primed DC or calamenene-primed DC enhanced the T cell stimulatory capacity in an allo MLR (allogeneic mixed lymphocyte reaction). Naïve T cells co-cultured with allogeneic M1-primed DC, M4-primed DC, T-cadinol-primed DC or calamenene-primed DC turned into typical Th1 cells, which produced large quantities of IFN-γ and released small amounts of IL-4 depending on IL-12 secretion. In the CTL assay (cytotoxic T-lymphocyte assay), the production of IFN-γ and 51Cr release on M4-primed DC was more augmented than of immature DC or TNF-α-primed DC. These results suggest that M1, M4, T-cadinol and calamenene appear to be a good factor to induce DC maturation, or even better in some respect, for the use in clinical DC therapy to induce strong Th1 type immune responses.

Cholera toxin B subunit promotes the induction of regulatory T cells by preventing human dendritic cell maturation

2008 ◽  
Vol 84 (3) ◽  
pp. 661-668 ◽  
Author(s):  
Antonella D'Ambrosio ◽  
Manuela Colucci ◽  
Orsola Pugliese ◽  
Francesca Quintieri ◽  
Monica Boirivant
Keyword(s):  
T Cells ◽  
Dendritic Cell ◽  
Regulatory T Cells ◽  
Dendritic Cell Maturation ◽  
Cell Maturation ◽  
Cholera Toxin B Subunit ◽  
Human Dendritic Cell ◽  
Toxin B ◽  
Cholera Toxin B ◽  
B Subunit

scholarly journals Distinct PKC-mediated posttranscriptional events set cytokine production kinetics in CD8+ T cells

2017 ◽  
Vol 114 (36) ◽  
pp. 9677-9682 ◽  
Author(s):  
Fiamma Salerno ◽  
Nahuel A. Paolini ◽  
Regina Stark ◽  
Marieke von Lindern ◽  
Monika C. Wolkers
Keyword(s):  
T Cells ◽  
Mrna Stability ◽  
Cytokine Production ◽  
De Novo ◽  
Translation Efficiency ◽  
Mrna Stabilization ◽  
Relative Contribution ◽  
Production Kinetics ◽  
Tnf Α ◽  
Ifn Γ

Effective T cell responses against invading pathogens require the concerted production of three key cytokines: TNF-α, IFN-γ, and IL-2. The cytokines functionally synergize, but their production kinetics widely differ. How the differential timing of expression is regulated remains, however, poorly understood. We compared the relative contribution of transcription, mRNA stability, and translation efficiency on cytokine production in murine effector and memory CD8+ T cells. We show that the immediate and ample production of TNF-α is primarily mediated by translation of preformed mRNA through protein kinase C (PKC)-induced recruitment of mRNA to polyribosomes. Also, the initial production of IFN-γ uses translation of preformed mRNA. However, the magnitude and subsequent expression of IFN-γ, and of IL-2, depends on calcium-induced de novo transcription and PKC-dependent mRNA stabilization. In conclusion, PKC signaling modulates translation efficiency and mRNA stability in a transcript-specific manner. These cytokine-specific regulatory mechanisms guarantee that T cells produce ample amounts of cytokines shortly upon activation and for a limited time.

Trauma-hemorrhage inhibits splenic dendritic cell proinflammatory cytokine production via a mitogen-activated protein kinase process

2008 ◽  
Vol 294 (3) ◽  
pp. C754-C764 ◽  
Author(s):  
Takashi Kawasaki ◽  
Mashkoor A. Choudhry ◽  
Martin G. Schwacha ◽  
Satoshi Fujimi ◽  
James A. Lederer ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Cytokine Production ◽  
Mitogen Activated Protein Kinase ◽  
Sham Operation ◽  
Dc Functions ◽  
Mapk Activation ◽  
Midline Laparotomy ◽  
Shed Blood ◽  
Splenic Dendritic Cell ◽  
Mitogen Activated Protein

Although splenic dendritic cell (DC) functions are markedly altered following trauma-hemorrhage, the mechanism(s) responsible for the altered DC functions remains unknown. We hypothesized that trauma-hemorrhage inhibits DC function via suppressing toll-like receptor 4 (TLR4) expression and mitogen-activated protein kinases (MAPKs). To examine this, male C3H/HeN (6–8 wk) mice were randomly assigned to sham operation or trauma-hemorrhage. Trauma-hemorrhage was induced by midline laparotomy and ∼90 min of hypotension [blood pressure (BP) 35 mmHg], followed by fluid resuscitation (4× the shed blood volume in the form of Ringer lactate). Two hours later, mice were euthanized, splenic DCs were isolated, and the changes in their MAPK activation, TLR4-MD-2 expression, and ability to produce cytokines were measured. The results indicate that trauma-hemorrhage downregulated the lipopolysaccharide (LPS)-induced MAPK activation in splenic DCs. In addition to the decrease in MAPK activation, surface expression of TLR4-MD-2 was suppressed following trauma-hemorrhage. Furthermore, LPS-induced cytokine production from splenic DCs was also suppressed following trauma-hemorrhage. These findings thus suggest that the decrease in TLR4-MD-2 and MAPK activation may contribute to the LPS hyporesponsiveness of splenic DCs following trauma-hemorrhage. Hyporesponsiveness of splenic DCs was also found after stimulation with the TLR2 agonist zymosan. Our results may thus explain the profound immunosuppression that is known to occur under those conditions.

scholarly journals Regional CNS responses to IFN-γ determine lesion localization patterns during EAE pathogenesis

2008 ◽  
Vol 205 (11) ◽  
pp. 2633-2642 ◽  
Author(s):  
Jason R. Lees ◽  
Paul T. Golumbek ◽  
Julia Sim ◽  
Denise Dorsey ◽  
John H. Russell
Keyword(s):  
Spinal Cord ◽  
T Cells ◽  
Brain Stem ◽  
Clinical Outcomes ◽  
Clinical Symptoms ◽  
Inflammatory Cells ◽  
Th1 Cells ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Ifn Γ

The localization of inflammatory foci within the cerebellum is correlated to severe clinical outcomes in multiple sclerosis (MS). Previous studies of experimental autoimmune encephalomyelitis (EAE), a model of MS, revealed distinct clinical outcomes correlated with the capacity of the animal to produce IFN-γ. Outcomes were linked to localization of inflammatory cells in either the spinal cord (wild type [WT]) or the cerebellum and brain stem (IFN-γ deficient). We demonstrate, using an adoptive transfer system, that the ability of the central nervous system (CNS) to sense pathogenic T cell–produced IFN-γ during EAE initiation determines the sites of CNS pathogenesis. Transfer of WT Th1 cells into IFN-γ receptor–deficient mice results in pathogenic invasion of the brain stem and cerebellum with attendant clinical symptoms, which are identical to the disease observed after transfer of IFN-γ–deficient T cells to WT hosts. Inflammation of the spinal cord associated with classical EAE is abrogated in both IFN-γ–deficient systems. Cotransfer of CNS antigen-specific WT Th1 cells with IFN-γ–deficient T cells is sufficient to restore spinal cord invasion and block cerebellar and brain stem invasion. These data demonstrate that interaction between IFN-γ and host CNS cells during the initiation of EAE can selectively promote or suppress neuroinflammation and pathogenesis.

scholarly journals An allergen-fused dendritic cell-binding peptide enhances in vitro proliferation of equine T-cells and cytokine production

2021 ◽  
pp. 110351
Author(s):  
Anja Ziegler ◽  
Judith Olzhausen ◽  
Eman Hamza ◽  
Ana Stojiljkovic ◽  
Michael H. Stoffel ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cell ◽  
Cytokine Production ◽  
Cell Binding ◽  
In Vitro Proliferation ◽  
Binding Peptide

scholarly journals CXCL12-CXCR4-Mediated Chemotaxis Supports Accumulation of Mucosal-Associated Invariant T Cells Into the Liver of Patients With PBC

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhilei Chen ◽  
Suying Liu ◽  
Chengmei He ◽  
Jinlei Sun ◽  
Li Wang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Cytokine Production ◽  
Immunofluorescence Staining ◽  
Primary Biliary Cholangitis ◽  
Hepatic Hemangioma ◽  
Cxcr4 Antagonist ◽  
Mait Cells ◽  
Ifn Γ ◽  
Invariant T Cells

Objectives: To explore the potential role of CD3+CD8+CD161high TCRVα7.2+ mucosal-associated invariant T (MAIT) cells in the pathogenesis of primary biliary cholangitis (PBC).Methods: We enrolled 55 patients with PBC, 69 healthy controls (HCs), and 8 patients with hepatic hemangioma. Circulating MAIT cells and their chemokine receptor profiles and cytokine production were quantified using flow cytometry. Liver-resident MAIT cells were examined by immunofluorescence staining. CXCL12-mediated chemotaxis of MAIT cells was measured using a transwell migration assay. Plasma interleukin (IL)-18 was measured using ELISA, and cytokine production in IL-18-stimulated MAIT cells was detected using flow cytometry.Result: Peripheral MAIT cells were found to be significantly lower in patients with PBC (3.0 ± 3.2% vs. 9.4 ± 8.0%, p &lt; 0.01) and negatively correlated with alkaline phosphatase (ALP) levels (r = −0.3209, p &lt; 0.05). Liver immunofluorescence staining suggested that MAIT cells might accumulate in PBC liver. MAIT cells from patients with PBC expressed higher levels of CXCR4 (84.8 ± 18.0% vs. 58.7 ± 11.4%, p &lt; 0.01), and the expression of CXCL12 was higher in PBC liver. CXCL12 promoted MAIT cell chemotaxis (70.4 ± 6.8% vs. 52.2 ± 3.5%, p &lt; 0.01), which was attenuated by CXCR4 antagonist. MAIT cells from PBC produced significantly more interferon-γ (IFN-γ) (88.3 ± 4.2% vs. 64.2 ± 10.1%, p &lt; 0.01), tumor necrosis factor-α (TNF-α) (93.0 ± 1.1% vs. 80.1 ± 5.3%, p &lt; 0.01), Granzyme B (89.3 ± 3.3% vs. 72.1 ± 7.0%, p &lt; 0.01), and perforin (46.8 ± 6.6% vs. 34.8 ± 7.7%, p &lt; 0.05). MAIT cells from PBC expressed higher levels of IL18-Rα (83.8 ± 10.2% vs. 58.3 ± 8.7%, p &lt; 0.01). Plasma IL-18 was more abundant in patients with PBC (286.8 ± 75.7 pg/ml vs. 132.9 ± 78.1 pg/ml, p &lt; 0.01). IL-18 promoted IFN-γ production in MAIT cells (74.9 ± 6.6% vs. 54.7 ± 6.7%, p &lt; 0.01), which was partially attenuated by blocking IL-18R (68.6 ± 8.3% vs. 43.5 ± 4.2%, p &lt; 0.01).Conclusion: Mucosal-associated invariant T cells from patients with PBC accumulated in the liver via CXCL12-CXCR4-mediated chemotaxis, produced pro-inflammatory cytokines, and contributed to portal inflammation, which was potentially mediated by elevated IL-18. Targeting MAIT cells might be a therapeutic approach for PBC.

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