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1.
J Autoimmun ; 75: 39-49, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27470005

ABSTRACT

Plasmacytoid dendritic cells (pDCs) have been shown to both mediate and prevent autoimmunity, and the regulation of their immunogenic versus tolerogenic functions remains incompletely understood. Here we demonstrate that, compared to other cells, pDCs are the major expressors of Indoleamine-2,3-dioxygenase (IDO) in steady-state lymph nodes (LNs). IDO expression by LN pDCs was closely dependent on MHCII-mediated, antigen-dependent, interactions with Treg. We further established that IDO production by pDCs was necessary to confer suppressive function to Tregs. During EAE development, IDO expression by pDCs was required for the generation of Tregs capable of dampening the priming of encephalitogenic T cell and disease severity. Thus, we describe a novel crosstalk between pDCs and Tregs: Tregs shape tolerogenic functions of pDCs prior to inflammation, such that pDCs in turn, promote Treg suppressive functions during autoimmunity.


Subject(s)
Autoimmunity/immunology , Dendritic Cells/immunology , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Autoimmunity/genetics , Cells, Cultured , Coculture Techniques , Dendritic Cells/metabolism , Encephalomyelitis, Autoimmune, Experimental/enzymology , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/immunology , Flow Cytometry , Gene Expression Regulation, Enzymologic , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class II/metabolism , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Lymph Nodes/enzymology , Lymph Nodes/immunology , Mice, Inbred C57BL , Mice, Transgenic , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes, Regulatory/metabolism
2.
J Autoimmun ; 67: 8-18, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26341385

ABSTRACT

Plasmacytoid dendritic cells (pDCs) exhibit both innate and adaptive functions. In particular they are the main source of type I IFNs and directly impact T cell responses through antigen presentation. We have previously demonstrated that during experimental autoimmune encephalomyelitis (EAE) initiation, myelin-antigen presentation by pDCs is associated with suppressive Treg development and results in attenuated EAE. Here, we show that pDCs transferred during acute disease phase confer recovery from EAE. Clinical improvement is associated with migration of injected pDCs into inflamed CNS and is dependent on the subsequent and selective chemerin-mediated recruitment of endogenous pDCs to the CNS. The protective effect requires pDC pre-loading with myelin antigen, and is associated with the modulation of CNS-infiltrating pDC phenotype and inhibition of CNS encephalitogenic T cells. This study may pave the way for novel pDC-based cell therapies in autoimmune diseases, aiming at specifically modulating pathogenic cells that induce and sustain autoimmune inflammation.


Subject(s)
Adoptive Transfer , Chemotaxis/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Animals , Autoantigens/immunology , Cell- and Tissue-Based Therapy , Chemokines/metabolism , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/therapy , Intercellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Knockout , Myelin Sheath/immunology , Receptors, Chemokine , Receptors, G-Protein-Coupled/metabolism , Spinal Cord/immunology , Spinal Cord/metabolism , Spinal Cord/pathology
3.
Infect Immun ; 79(4): 1638-46, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21300776

ABSTRACT

To investigate the role of Toll-like receptor 9 (TLR9) in innate immunity to Mycobacterium avium, TLR9, TLR2, and MyD88 knockout (KO) mice were infected with this bacterium. Bacterial burdens were higher in the spleens, livers, and lungs of infected TLR9 KO mice than in those of C57BL/6 mice, indicating that TLR9 is required for efficient control of M. avium infection. However, TLR9 KO or TLR2 KO spleen cells displayed normal M. avium-induced tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) responses. This finding was confirmed by determining the number of splenic CD4(+) T cells producing IFN-γ by flow cytometry. Furthermore, TLR2 and MyD88, but not TLR9, played a major role in interleukin-12 and TNF-α production by M. avium-infected macrophages and dendritic cells (DCs). We also found that major histocompatibility complex class II molecule expression on DCs is regulated by TLR2 and MyD88 signaling but not by TLR9. Finally, lack of TLR9, TLR2, or MyD88 reduced the numbers of macrophages, epithelioid cells, and lymphocytes in M. avium-induced granulomas but only MyD88 deficiency affected the number of liver granulomas. In summary, our data demonstrated that the involvement of TLR9 in the control of M. avium infection is not related to the induction of Th1 responses.


Subject(s)
Th1 Cells/immunology , Toll-Like Receptor 9/immunology , Tuberculosis/immunology , Animals , Cell Separation , Dendritic Cells/immunology , Dendritic Cells/microbiology , Flow Cytometry , Histocompatibility Antigens Class II/biosynthesis , Histocompatibility Antigens Class II/immunology , Lymphocyte Activation/immunology , Macrophages/immunology , Macrophages/metabolism , Macrophages/microbiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mycobacterium avium/immunology , Myeloid Differentiation Factor 88/immunology , Reverse Transcriptase Polymerase Chain Reaction , Th1 Cells/metabolism , Toll-Like Receptor 2/immunology , Toll-Like Receptor 9/metabolism , Tuberculosis/pathology , Tuberculosis/veterinary
4.
Life Sci Alliance ; 1(6): e201800164, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30584641

ABSTRACT

How lymph node stromal cells (LNSCs) shape peripheral T-cell responses remains unclear. We have previously demonstrated that murine LNSCs, lymphatic endothelial cells (LECs), blood endothelial cells (BECs), and fibroblastic reticular cells (FRCs) use the IFN-γ-inducible promoter IV (pIV) of the MHC class II (MHCII) transactivator CIITA to express MHCII. Here, we show that aging mice (>1 yr old) in which MHCII is abrogated in LNSCs by the selective deletion of pIV exhibit a significant T-cell dysregulation in LNs, including defective Treg and increased effector CD4+ and CD8+ T-cell frequencies, resulting in enhanced peripheral organ T-cell infiltration and autoantibody production. The proliferation of LN-Tregs interacting with LECs increases following MHCII up-regulation by LECs upon aging or after exposure to IFN-γ, this effect being abolished in mice in which LECs lack MHCII. Overall, our work underpins the importance of LNSCs, particularly LECs, in supporting Tregs and T-cell tolerance.

5.
Front Immunol ; 6: 459, 2015.
Article in English | MEDLINE | ID: mdl-26441964

ABSTRACT

Although autophagy is a process that has been studied for several years its link with antigen presentation and T cell immunity has only recently emerged. Autophagy, which means "self-eating," is important to maintain cell homeostasis and refers to a collection of mechanisms that delivers intracellular material for degradation into lysosomes. Among them, macroautophagy pathway has many implications in different biological processes, including innate and adaptive immunity. In particular, macroautophagy can provide a substantial source of intracellular antigens for loading onto MHC class II molecules using the alternative MHC class II pathway. Through autophagosomes, endogenous self-antigens as well as antigens derived from intracellular pathogens can be delivered to MHC class II compartment and presented to CD4(+) T cells. The pathway will, therefore, impact both peripheral T cell tolerance and the pathogen specific immune response. This review will describe the contribution of autophagy to intracellular presentation of endogenous self- or pathogen-derived antigens via MHC class II and its consequences on CD4(+) T cell responses.

6.
J Exp Med ; 211(6): 1153-66, 2014 Jun 02.
Article in English | MEDLINE | ID: mdl-24842370

ABSTRACT

Dendritic cells (DCs), and more recently lymph node stromal cells (LNSCs), have been described to tolerize self-reactive CD8(+) T cells in LNs. Although LNSCs express MHCII, it is unknown whether they can also impact CD4(+) T cell functions. We show that the promoter IV (pIV) of class II transactivator (CIITA), the master regulator of MHCII expression, controls endogenous MHCII expression by LNSCs. Unexpectedly, LNSCs also acquire peptide-MHCII complexes from DCs and induce CD4(+) T cell dysfunction by presenting transferred complexes to naive CD4(+) T cells and preventing their proliferation and survival. Our data reveals a novel, alternative mechanism where LN-resident stromal cells tolerize CD4(+) T cells through the presentation of self-antigens via transferred peptide-MHCII complexes of DC origin.


Subject(s)
Antigens/immunology , CD4-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Immune Tolerance/immunology , Lymph Nodes/immunology , Stromal Cells/immunology , Animals , Antigen Presentation/immunology , CD4-Positive T-Lymphocytes/metabolism , Cell Proliferation , Cells, Cultured , Dendritic Cells/metabolism , Flow Cytometry , Gene Expression/drug effects , Gene Expression/immunology , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class II/metabolism , Interferon-gamma/immunology , Interferon-gamma/pharmacology , Lymph Nodes/cytology , Lymph Nodes/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Nuclear Proteins/genetics , Nuclear Proteins/immunology , Nuclear Proteins/metabolism , Peptides/immunology , Peptides/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Stromal Cells/metabolism , Trans-Activators/genetics , Trans-Activators/immunology , Trans-Activators/metabolism
7.
Cell Rep ; 1(3): 191-9, 2012 Mar 29.
Article in English | MEDLINE | ID: mdl-22832193

ABSTRACT

Tumor expression of the lymphangiogenic factor VEGF-C is correlated with metastasis and poor prognosis, and although VEGF-C enhances transport to the draining lymph node (dLN) and antigen exposure to the adaptive immune system, its role in tumor immunity remains unexplored. Here, we demonstrate that VEGF-C promotes immune tolerance in murine melanoma. In B16 F10 melanomas expressing a foreign antigen (OVA), VEGF-C protected tumors against preexisting antitumor immunity and promoted local deletion of OVA-specific CD8(+) T cells. Naive OVA-specific CD8(+) T cells, transferred into tumor-bearing mice, were dysfunctionally activated and apoptotic. Lymphatic endothelial cells (LECs) in dLNs cross-presented OVA, and naive LECs scavenge and cross-present OVA in vitro. Cross-presenting LECs drove the proliferation and apoptosis of OVA-specific CD8(+) T cells ex vivo. Our findings introduce a tumor-promoting role for lymphatics in the tumor and dLN and suggest that lymphatic endothelium in the local microenvironment may be a target for immunomodulation.


Subject(s)
Antigens, Neoplasm/immunology , Cross-Priming/immunology , Immune Tolerance/immunology , Lymph Nodes/immunology , Melanoma, Experimental/immunology , Vascular Endothelial Growth Factor C/metabolism , Animals , Antigen Presentation/immunology , Apoptosis/immunology , CD8-Positive T-Lymphocytes/immunology , Cancer Vaccines/immunology , Dendritic Cells/immunology , Endothelial Cells/metabolism , Histocompatibility Antigens Class I/immunology , Lymph Nodes/pathology , Lymphangiogenesis , Melanoma, Experimental/pathology , Melanoma, Experimental/prevention & control , Mice , Neoplasm Metastasis , Peptides/immunology , Stromal Cells/metabolism
8.
Immunol Lett ; 125(1): 72-7, 2009 Jun 30.
Article in English | MEDLINE | ID: mdl-19539649

ABSTRACT

Schistosoma mansoni schistosomula are the most susceptible parasite life stage to host immune system attack. Complex host-parasite interactions take place on Schistosoma tegument, which is a unique double membrane structure involved in nutrition and immune evasion. Herein, we have demonstrated that schistosomula tegument (Smteg) activates Dendritic cells to produce IL-12p40, TNF-alpha and also to up-regulate the co-stimulatory molecules CD40 and CD86. Moreover, using DCs derived from MyD88-, TLR2-, TLR4- and TLR9-deficient mice we have shown that the ability of Smteg to activate DCs to produce IL-12 and TNF-alpha involves TLR4/Smteg interaction and MyD88 signaling pathway. Finally, our findings lead us to conclude that TLR4 is a key receptor involved in Smteg induction of pro-inflammatory cytokines.


Subject(s)
Dendritic Cells/immunology , Host-Parasite Interactions/immunology , Interleukin-12 Subunit p40/biosynthesis , Myeloid Differentiation Factor 88/immunology , Schistosoma mansoni/immunology , Toll-Like Receptor 4/immunology , Tumor Necrosis Factor-alpha/biosynthesis , Animals , B7-2 Antigen/immunology , B7-2 Antigen/metabolism , CD40 Antigens/immunology , CD40 Antigens/metabolism , Interleukin-12 Subunit p40/immunology , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloid Differentiation Factor 88/genetics , Signal Transduction/immunology , Toll-Like Receptor 4/genetics , Tumor Necrosis Factor-alpha/immunology , Up-Regulation/immunology
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