IL-6 Produced by Type I IFN DC Controls IFN-γ Production during the MLR by Blocking the Suppressive Effect of Regulatory T Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3797-3797
Author(s):  
Olivier Detournay ◽  
Naima Mazouz ◽  
Michel Goldman ◽  
Michel Toungouz
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Mrna Level ◽  
Suppressive Effect ◽  
Poly I:C ◽  
Type I ◽  
Type I Ifn ◽  
Effector Cells ◽  
Gm Csf ◽  
Ifn Γ

Abstract The dendritic cell family is composed of different subsets able to differentially govern the immune response. Their potent antigen presenting properties make them an attractive candidate for immunization against pathogens or cancer. In that setting, the recently characterized type I IFN DCs present interesting features including a higher expression of molecules involved in antigen presentation and the ability to trigger both the cellular and humoral arms of the immune responses. In view of the pivotal role of regulatory T cells in limiting the effectiveness of effector cells, we analyzed the interactions between these cells and type I IFN DC. DC generated from monocytes in the presence of IFN-β and IL-3 (DCI3) were activated by the maturation agent poly I:C and compared with the classical myeloid DC generated in the presence of GM-CSF and IL-4 (DCG4). Despite the release of lower amounts of IL-12 after maturation, DCI3 were able to induce a higher IFN-γ production by T lymphocytes during the MLR. Analysis at the mRNA level disclosed that DCI3 over transcribed the IL-6 gene leading to the release of high amounts of the protein both after the maturation process and during the MLR itself. Neutralization of IL-6 revealed that this cytokine specifically contributed to the IFN-γ release induced by DCI3. Finally, depletion of CD25+ T cells prior to the MLR identified these cells as a target for IL-6. We conclude from these results that DCI3 are endowed with the unique property of blocking the suppressive effect of regulatory T cells through high IL-6 production during the MLR. This novel mechanism of T cell control is relevant for the use of this DC type in vaccination strategies.

IL-6 Produced by Type I IFN DC Controls IFN-γ Production by Regulating the Suppressive Effect of CD4+ CD25+ Regulatory T Cells

2005 ◽  
Vol 66 (5) ◽  
pp. 460-468 ◽  
Author(s):  
Olivier Detournay ◽  
Naima Mazouz ◽  
Michel Goldman ◽  
Michel Toungouz
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Suppressive Effect ◽  
Type I ◽  
Type I Ifn ◽  
Ifn Γ

scholarly journals P01.02 TLR-mediated suppression of the CCL22-CCR4 axis as a new target for tumor immunotherapy

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A3.2-A4
Author(s):  
J Grün ◽  
I Piseddu ◽  
C Perleberg ◽  
N Röhrle ◽  
S Endres ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Regulatory T Cells ◽  
Type I ◽  
List Type ◽  
Gm Csf

BackgroundUnmethylated CpG-DNA is a potent ligand for the endosomal Toll-like-receptor-9, important for the immune activation to pathogen-associated molecules.1 CpG and other TLR-ligands show effective immunotherapeutic capacities in cancer treatment by inducing an antitumorigenic immunity.2 They are able to reduce tumor progression by reduction of intratumoral secretion of the immunoregulating chemokine CCL223 and subsequent recruitment of immunosuppressive regulatory T cells (Treg), which express CCR4 the only so far known receptor for CCL22.4 Our recent work has shown that CCL22 secretion by dendritic cells (DC) in the lymph node, mediates tolerance by inducing DC-Treg contacts.5 Indeed, in the absence of CCL22, immune responses to vaccination were stronger and resulted in tumor rejection.6 Therefore, we are aiming to investigate the effects of TLR-ligands on systemic CCL22 levels, elucidating all involved mechanisms to identify new targets for cancer immunotherapy.Materials and MethodsT, B and CD11c+ DCs of wildtype (wt) and RAG1-/- mice were isolated from splenocytes by magnetic-activated cell sorting for in vitro assays. Different co-cultures were incubated with CpG and GM-CSF, known as an CCL22 inducer.5 For in vivo experiments, wt mice were treated with CpG, R484 or poly(I:C) alone and in combination with GM-CSF. CCL22-levels in a number of organs were analyzed.ResultsAnalyzing the different immune cell compartments in vitro, we found that DCs in whole splenocytes secrete CCL22 during culture while DC cultured alone showed no CCL22 secretion. When treated with CpG, CCL22-levels were reduced in splenocytes, while it was induced in DC culture alone. The same results were seen when RAG splenocytes, that lack functional B and T cells, were cultured with CpG. CpG treated B cells were able to suppress CCL22 secretion by DC unlike T cells alone. Co-cultures of T and B cells treated with CpG, however, induced the strongest CCL22 suppression in DC. In vivo, we could show that all TLR ligands tested reduced CCL22 in a number of organs significantly. Furthermore, CpG showed the strongest suppression of CCL22 even in the presence of the CCL22 inducer GM-CSF.5ConclusionsWe could show that B cells with T cells mediate CCL22 suppression by TLR ligands. The fact that CpG was able to reduce CCL22 levels even in the presence of the inducer GM-CSF demonstrates the potent CCL22 suppressive capacity of TLR ligands.ReferencesO’Neill LA, et al. The history of toll-like receptors – redefining innate immunity. Nat Rev Immunol 2013;13(6):453–60.Rothenfusser S, et al. Recent advances in immunostimulatory CpG oligonucleotides. Curr Opin Mol Ther 2003;5(2):98–106.Wang S, et al. Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells. Proc Natl Acad Sci U S A 2016;113(46): E7240–E7249.Rapp M, et al. CCL22 controls immunity by promoting regulatory T cell communication with dendritic cells in lymph nodes. J Exp Med 2019;216(5):1170–1181.Piseddu I, et al. Constitutive expression of CCL22 is mediated by T cell-derived GM-CSF. J Immunol 2020;205(8):2056–2065.Anz D, et al. Suppression of intratumoral CCL22 by type i interferon inhibits migration of regulatory T cells and blocks cancer progression. Cancer Res 2015;75(21):4483–93.Disclosure InformationJ. Grün: None. I. Piseddu: None. C. Perleberg: None. N. Röhrle: None. S. Endres: None. D. Anz: None.

scholarly journals Type I IFN gene delivery suppresses regulatory T cells within tumors

2014 ◽  
Vol 21 (12) ◽  
pp. 532-541 ◽  
Author(s):  
H Hashimoto ◽  
R Ueda ◽  
K Narumi ◽  
Y Heike ◽  
T Yoshida ◽  
...  
Keyword(s):  
T Cells ◽  
Gene Delivery ◽  
Regulatory T Cells ◽  
Type I ◽  
Type I Ifn

scholarly journals Idiotype Immunization Combined With Granulocyte-Macrophage Colony-Stimulating Factor in Myeloma Patients Induced Type I, Major Histocompatibility Complex–Restricted, CD8- and CD4-Specific T-Cell Responses

Blood ◽  
1998 ◽  
Vol 91 (7) ◽  
pp. 2459-2466 ◽  
Author(s):  
Anders Österborg ◽  
Qing Yi ◽  
Lotta Henriksson ◽  
Jan Fagerberg ◽  
Susanne Bergenbrant ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Type I ◽  
Gm Csf ◽  
Histocompatibility Complex ◽  
Macrophage Colony Stimulating Factor ◽  
Ifn Γ ◽  
Macrophage Colony ◽  
Stimulating Factor

Idiotypic structures expressed on the myeloma Ig protein might be regarded as a tumor-specific antigen. Five patients with IgG myeloma were immunized with the purified serum M-component by repeated intradermal injections together with soluble granulocyte-macrophage colony-stimulating factor (GM-CSF). All patients developed an idiotype (Id)-specific T-cell immunity, defined as blood T cells predominantly secreting interferon-γ (IFN-γ) and interleukin-2 (IL-2) (type I cells). Id-specific DNA synthesis was induced in one patient. Delayed-type hypersensitivity against the Id was not evoked. The specific IFN-γ/IL-2 T-cell response was inhibited (46% to 100%) by a major histocompatibility complex (MHC) class I monoclonal antibody (MoAb) in all five patients. A 5% to 37% inhibition by an MHC class II MoAb was seen in four patients. CD4+ as well as CD8+ T cells enriched by magnetic microbeads contained Id-specific cells. The T cells recognized peptides corresponding to the complementarity-determining regions 1, 2, and 3 of the heavy chain of the Id. There was a transient rise of B cells producing IgM anti-idiotypic antibodies in all patients. The results indicate that immunization of myeloma patients using the autologous M-component and soluble GM-CSF may evoke an Id-specific predominantly MHC class I–restricted type I T-cell response.

scholarly journals Idiotype Immunization Combined With Granulocyte-Macrophage Colony-Stimulating Factor in Myeloma Patients Induced Type I, Major Histocompatibility Complex–Restricted, CD8- and CD4-Specific T-Cell Responses

Blood ◽  
1998 ◽  
Vol 91 (7) ◽  
pp. 2459-2466 ◽  
Author(s):  
Anders Österborg ◽  
Qing Yi ◽  
Lotta Henriksson ◽  
Jan Fagerberg ◽  
Susanne Bergenbrant ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Type I ◽  
Gm Csf ◽  
Histocompatibility Complex ◽  
Macrophage Colony Stimulating Factor ◽  
Ifn Γ ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Idiotypic structures expressed on the myeloma Ig protein might be regarded as a tumor-specific antigen. Five patients with IgG myeloma were immunized with the purified serum M-component by repeated intradermal injections together with soluble granulocyte-macrophage colony-stimulating factor (GM-CSF). All patients developed an idiotype (Id)-specific T-cell immunity, defined as blood T cells predominantly secreting interferon-γ (IFN-γ) and interleukin-2 (IL-2) (type I cells). Id-specific DNA synthesis was induced in one patient. Delayed-type hypersensitivity against the Id was not evoked. The specific IFN-γ/IL-2 T-cell response was inhibited (46% to 100%) by a major histocompatibility complex (MHC) class I monoclonal antibody (MoAb) in all five patients. A 5% to 37% inhibition by an MHC class II MoAb was seen in four patients. CD4+ as well as CD8+ T cells enriched by magnetic microbeads contained Id-specific cells. The T cells recognized peptides corresponding to the complementarity-determining regions 1, 2, and 3 of the heavy chain of the Id. There was a transient rise of B cells producing IgM anti-idiotypic antibodies in all patients. The results indicate that immunization of myeloma patients using the autologous M-component and soluble GM-CSF may evoke an Id-specific predominantly MHC class I–restricted type I T-cell response.

Clinical-Grade Type I IFN-DC Differentiated in the Presence of Either IL-3 or GM-CSF Show Similar Phenotypic and Functional Proprieties.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3798-3798
Author(s):  
Naima Mazouz ◽  
Olivier Detournay ◽  
Joelle Rennesson ◽  
Micheline Lambermont ◽  
Arnaud Marchant ◽  
...  
Keyword(s):  
Therapeutic Vaccine ◽  
Hla Class I ◽  
Poly I:C ◽  
Type I ◽  
Clinical Grade ◽  
Type I Ifn ◽  
Gm Csf ◽  
Type I Ifns ◽  
Similar Phenotype ◽  
New Type

Abstract Despite limited clinical efficacy in large trials, dendritic cells (DC)-based immunization has yielded impressive responses in some patients. Key questions remain to be solved in order to optimize this therapeutic vaccine. Among them, the nature of the DC used and its state of maturation are pivotal. Besides myeloid DCs which are the cells essentially used in clinical trials, a new type of DC has been described resulting from the differentiation of monocytes in the presence of type I IFNs. In the present study, we analyzed the features of clinical grade type I IFN DC generated in the presence of either IL-3 (IL-3- DCs) or GM-CSF (GM-CSF-DCs) and compared their capacity to respond to poly I:C, a double-stranded RNA analog that mimics viral infection. The two DC types disclosed a similar immunophenotype characterized by high levels of costimulatory molecules, CCR7, HLA-class-I and class-II molecules. After poly I:C maturation, both DC types displayed a marked upregulation of CD80, CD83 and CD86. In addition, poly I:C stimulated them to secrete IFN-α IL-12 p70, IL-12 p40 and IL-6. Both DC types elicited potent allogeneic reactions. Priming of autologous T cells by IL-3-DCs or GM-CSF-DCs pulsed with an HLA-A2 restricted melan-A derived peptide, lead to expansion of melan-A specific CTL secreting high levels of IFN-γ and displaying a phenotype of memory cells. We conclude that mature clinical grade IL-3-DCs and GM-CSF-DCs share similar phenotype and functional properties including the capacity to prime Ag-specific CTL.

scholarly journals Role of CD4+Foxp3+Regulatory T Cells in Protection Induced by a Live Attenuated, Replicating Type I Vaccine Strain of Toxoplasma gondii

2015 ◽  
Vol 83 (9) ◽  
pp. 3601-3611 ◽  
Author(s):  
Haroon Akbar ◽  
Isabelle Dimier-Poisson ◽  
Nathalie Moiré
Keyword(s):  
T Cells ◽  
Toxoplasma Gondii ◽  
Regulatory T Cells ◽  
T Regulatory Cells ◽  
Interleukin 2 ◽  
Type I ◽  
Content Type ◽  
Effector Cells ◽  
Cytokine Responses

Vaccination with the live attenuatedToxoplasma gondiiMic1.3KO strain induced long-lasting immunity against challenge withToxoplasma gondiitype I and type II strains. The involvement of regulatory T cells (Tregs) in the protection mechanism was investigated. Intraperitoneal injection of Mic1.3KO induced a weak and transient influx of CD4+Foxp3+T regulatory cells followed by recruitment/expansion of CD4+Foxp3−CD25+effector cells and control of the parasite at the site of infection. The local and systemic cytokine responses associated with this recruitment of Tregs were of the TH1/Treg-like type. In contrast, injection of RH, the wild-type strain from which the vaccinal strain is derived, induced a low CD4+Foxp3+cell influx and uncontrolled multiplication of the parasites at this local site, followed by death of the mice. The associated local and systemic cytokine responses were of the TH1/TH17-like type. In addition,in vivoTreg induction in RH-infected mice with interleukin-2 (IL-2)/anti-IL-2 complexes induced control of the parasite and a TH1/Treg cytokine response similar to the response after Mic1.3KO vaccination. These results suggest that Tregs may contribute to the protective response after vaccination with Mic1.3KO.

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