CD1d on Myeloid Dendritic Cells Stimulates Cytokine Secretion from and Cytolytic Activity of Vα24JαQ T Cells: A Feedback Mechanism for Immune Regulation

ABSTRACT We have previously shown that very few rotavirus (RV)-specific T cells that secrete gamma interferon circulate in recently infected and seropositive adults and children. Here, we have studied the interaction of RV with myeloid immature (IDC) and mature dendritic cells (MDC) in vitro. RV did not induce cell death of IDC or MDC and induced maturation of between 12 and 48% of IDC. Nonetheless, RV did not inhibit the maturation of IDC or change the expression of maturation markers on MDC. After treatment with RV, few IDC expressed the nonstructural viral protein NSP4. In contrast, a discrete productive viral infection was shown in MDC of a subset of volunteers, and between 3 and 46% of these cells expressed NSP4. RV-treated IDC secreted interleukin 6 (IL-6) (but not IL-1β, IL-8, IL-10, IL-12, tumor necrosis factor alpha, or transforming growth factor beta), and MDC released IL-6 and small amounts of IL-10 and IL-12p70. The patterns of cytokines secreted by T cells stimulated by staphylococcal enterotoxin B presented by MDC infected with RV or uninfected were comparable. The frequencies and patterns of cytokines secreted by memory RV-specific T cells evidenced after stimulation of peripheral blood mononuclear cells (PBMC) with RV were similar to those evidenced after stimulation of PBMC with RV-infected MDC. Finally, IDC treated with RV strongly stimulated naive allogeneic CD4+ T cells to secrete Th1 cytokines. Thus, although RV does not seem to be a strong maturing stimulus for DC, it promotes their capacity to prime Th1 cells.

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Compensatory roles of CD8+ T cells and plasmacytoid dendritic cells in gut immune regulation for reduced function of CD4+ Tregs

Oncotarget ◽

10.18632/oncotarget.7510 ◽

2016 ◽

Vol 7 (10) ◽

pp. 10947-10961 ◽

Cited By ~ 2

Author(s):

Young-In Kim ◽

Bo-Ra Lee ◽

Jae-Hee Cheon ◽

Bo-Eun Kwon ◽

Mi-Na Kweon ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd8 T Cells ◽

Immune Regulation ◽

Plasmacytoid Dendritic Cells

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Monomethyl fumarate treatment impairs maturation of human myeloid dendritic cells and their ability to activate T cells

Multiple Sclerosis Journal ◽

10.1177/1352458517740213 ◽

2017 ◽

Vol 25 (1) ◽

pp. 63-71 ◽

Cited By ~ 9

Author(s):

Maria Antonietta Mazzola ◽

Radhika Raheja ◽

Keren Regev ◽

Vanessa Beynon ◽

Felipe von Glehn ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Dimethyl Fumarate ◽

Nuclear Factor Κb ◽

Interleukin 17 ◽

Myeloid Dendritic Cells ◽

Gm Csf ◽

Monomethyl Fumarate ◽

And Function

Background: Dimethyl fumarate (DMF) and its active metabolite monomethyl fumarate (MMF) effectively lead to reduction in disease relapses and active magnetic resonance imaging (MRI) lesions. DMF and MMF are known to be effective in modulating T- and B-cell responses; however, their effect on the phenotype and function of human myeloid dendritic cells (mDCs) is not fully understood. Objective: To investigate the role of MMF on human mDCs maturation and function. Methods: mDCs from healthy controls were isolated and cultured in vitro with MMF. The effect of MMF on mDC gene expression was determined by polymerase chain reaction (PCR) array after in vitro MMF treatment. The ability of mDCs to activate T cells was assessed by in vitro co-culture system. mDCs from DMF-treated multiple sclerosis (MS) patients were analyzed by flow cytometry and PCR. Results: MMF treatment induced a less mature phenotype of mDCs with reduced expression of major histocompatibility complex class II (MHC-II), co-stimulatory molecules CD86, CD40, CD83, and expression of nuclear factor κB (NF-κB) subunits RELA and RELB. mDCs from DMF-treated MS patients also showed the same immature phenotype. T cells co-cultured with MMF-treated mDCs showed reduced proliferation with decreased production of interferon gamma (IFN-γ), interleukin-17 (IL-17), and granulocyte-macrophage colony-stimulating factor (GM-CSF) compared to untreated cells. Conclusion: We report that MMF can modulate immune response by affecting human mDC function.

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Introduction of Human Flt3-L and GM-CSF into Humanized Mice Enhances the Reconstitution and Maturation of Myeloid Dendritic Cells and the Development of Foxp3+CD4+ T Cells

Frontiers in Immunology ◽

10.3389/fimmu.2018.01042 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 8

Author(s):

Ryutaro Iwabuchi ◽

Shota Ikeno ◽

Mie Kobayashi-Ishihara ◽

Haruko Takeyama ◽

Manabu Ato ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Humanized Mice ◽

Myeloid Dendritic Cells ◽

Gm Csf

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NF-κB Blockade Induces Apoptosis and Decreases Costimulatory Molecules and IL-12 Secretion of Dendritic Cells, Altering DC Maturation: Role in Induction of Tolerance after Transplantation.

Blood ◽

10.1182/blood.v106.11.2465.2465 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2465-2465

Author(s):

Luis I. Sanchez Abarca ◽

Jose A. Perez-Simon ◽

Belen Blanco ◽

Norma Gutierrez ◽

Juan Mateos ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Allogeneic Transplantation ◽

Costimulatory Molecules ◽

Cytokine Secretion ◽

Gm Csf ◽

Hla Dr ◽

New Strategy ◽

Th1 Cytokine ◽

Dc Maturation

Abstract In steady state, dendritic cells (DC) are in an immature status and maintain tolerance to self antigens. By contrast, if DC maturation is stimulated, as it occurs in the proinflamatory milieu induced by allogeneic transplantation, they trigger effector and memory T cells and, for this reason, they play an essential role in the development of graft versus host disease (GVHD). DC maturation and survival is dependent on NF-kB. Thus, we explored the ability of the proteosome inhibitor bortezomib (B), which prevents Nuclear Factor kB (NF-kB) activation, to induce DC apoptosis and block maturation as a new strategy to prevent GVHD. DC were obtained from PBMN after culture with GM-CSF and IL-4 and were stimulated to maturate and express costimulatory molecules (CD80, CD83, CD86, CD40L) adding TNF and LPS. Even after this stimulation, B at doses ranging from 10 to 50 nM was able to decrease costimulatory molecules as well as HLA-DR expression, as assessed by flow cytometry. In addition, at 50 nM, B increased DC apoptosis (2650 vs 1404 anex/7AAD positive events among DC cultured with or w/o B, respectively; p=0.05). Moreover, B significantly decreased the production of IL-12, while IL10 secretion was unaffected (1,4% vs 6,2% DC cultured with or w/o B secreting IL-12, respectively; p=0.01). Cytokines and proinflamatory molecules genes expression profiling was also analysed by microarrays in DC cultured with or without B. Finally, after culture with bortezomib, DC were cocultured with T lymphocytes and, interestingly, allogeneic mixed lymphocyte reaction was markedly inhibited also inducing a decrease in Th1 cytokine secretion among T cells. In conclusion, bortezomib induces apoptosis and decreases DC maturation and cytokine secretion and favours tolerance to alloantigens. This new strategy based on DC therapy supports the use of proteosome inhibitors in the management of GVHD.

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The Balance in Chimerism between T Cells and Blood Dendritic Cells in Relapsed CML Patients Influences the Induction of Alloreactivity Following Donor Lymphocyte Infusion.

Blood ◽

10.1182/blood.v108.11.5139.5139 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5139-5139

Author(s):

Henriette Levenga ◽

Rob Woestenenk ◽

Antonius V.M.B. Schattenberg ◽

Frans Maas ◽

Joop H. Jansen ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Early Stage ◽

Chronic Phase ◽

Donor Lymphocyte Infusion ◽

Mixed Chimerism ◽

Myeloid Dendritic Cells ◽

Median Percentage ◽

Donor Chimerism ◽

Group 2

Abstract Donor lymphocyte infusions (DLI) after allogeneic stem cell transplantation induce complete remissions in 70 to 80% of patients with relapsed CML in chronic phase, but some patients do not respond sufficiently to DLI. We studied chimerism in subsets of immune cells in relation to the induction of alloreactivity. T cells and two subsets of DC (blood precursor myeloid dendritic cells [MDC] and blood precursor plasmacytoid dendritic cells [PDC]) were isolated from 15 relapsed CML-patients shortly before DLI for chimerism analysis. Furthermore, the absolute blood counts of DC-subsets were determined. Based on chimerism we identified three groups. Group 1 (4 patients) was complete donor chimeric in T cells and DC-subsets. These patients had an early stage of relapse and 3 of 4 patients attained a complete molecular remission (mCR) without significant GVHD. Group 2 (6 patients) was complete donor in T cells and mixed chimeric in DC-subsets. Median percentage of recipient MDC in 4 patients with mixed chimerism was 67% (range, 36%–72%). One patient was complete donor and one patient complete recipient chimeric in MDC. Median percentage of recipient PDC was 37% (range, 18%–58%) in 5 patients with mixed chimerism and in 1 patient PDC were complete recipient derived. All patients entered mCR, however in combination with GVHD in 4 and bone marrow hypoplasia in 3 patients. Group 3 (5 patients) had mixed chimerism in T cells and complete recipient chimerism in MDC in 4 of 5 patients. Only 2 patients entered mCR. Absolute DC numbers at the time of DLI did not predict the induction of an allo-immune response, however very low numbers of MDC and PDC were associated with progressive disease and a poor outcome. The combination of donor chimerism in T cells and mixed chimerism in DC-subsets in advanced relapse is associated with the most potent GVL effect following DLI. GVL and GVHD are separated in patients with an early relapse and donor chimerism in both T cells and DC-subsets. Finally, absolute DC numbers do not predict the strength of the alloresponse.

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