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1.
PLoS Pathog ; 9(6): e1003476, 2013.
Article in English | MEDLINE | ID: mdl-23825956

ABSTRACT

In the murine model of Leishmania major infection, resistance or susceptibility to the parasite has been associated with the development of a Th1 or Th2 type of immune response. Recently, however, the immunosuppressive effects of IL-10 have been ascribed a crucial role in the development of the different clinical correlates of Leishmania infection in humans. Since T cells and professional APC are important cellular sources of IL-10, we compared leishmaniasis disease progression in T cell-specific, macrophage/neutrophil-specific and complete IL-10-deficient C57BL/6 as well as T cell-specific and complete IL-10-deficient BALB/c mice. As early as two weeks after infection of these mice with L. major, T cell-specific and complete IL-10-deficient animals showed significantly increased lesion development accompanied by a markedly elevated secretion of IFN-γ or IFN-γ and IL-4 in the lymph nodes draining the lesions of the C57BL/6 or BALB/c mutants, respectively. In contrast, macrophage/neutrophil-specific IL-10-deficient C57BL/6 mice did not show any altered phenotype. During the further course of disease, the T cell-specific as well as the complete IL-10-deficient BALB/c mice were able to control the infection. Furthermore, a dendritic cell-based vaccination against leishmaniasis efficiently suppresses the early secretion of IL-10, thus contributing to the control of parasite spread. Taken together, IL-10 secretion by T cells has an influence on immune activation early after infection and is sufficient to render BALB/c mice susceptible to an uncontrolled Leishmania major infection.


Subject(s)
Dendritic Cells/immunology , Interleukin-10/immunology , Leishmania major/immunology , Leishmaniasis Vaccines/immunology , Leishmaniasis, Cutaneous/immunology , Th1 Cells/immunology , Th2 Cells/immunology , Animals , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-10/genetics , Interleukin-4/genetics , Interleukin-4/immunology , Leishmaniasis Vaccines/pharmacology , Leishmaniasis, Cutaneous/genetics , Leishmaniasis, Cutaneous/pathology , Lymph Nodes/immunology , Mice , Mice, Inbred BALB C , Mice, Knockout , Th1 Cells/pathology , Th2 Cells/pathology
2.
Immunity ; 28(4): 546-58, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18387831

ABSTRACT

The regulatory T (Treg) cells restrain immune responses through suppressor-function elaboration that is dependent upon expression of the transcription factor Foxp3. Despite a critical role for Treg cells in maintaining lympho-myeloid homeostasis, it remains unclear whether a single mechanism or multiple mechanisms of Treg cell-mediated suppression are operating in vivo and how redundant such mechanisms might be. Here we addressed these questions by examining the role of the immunomodulatory cytokine IL-10 in Treg cell-mediated suppression. Analyses of mice in which the Treg cell-specific ablation of a conditional IL-10 allele was induced by Cre recombinase knocked into the Foxp3 gene locus showed that although IL-10 production by Treg cells was not required for the control of systemic autoimmunity, it was essential for keeping immune responses in check at environmental interfaces such as the colon and lungs. Our study suggests that Treg cells utilize multiple means to limit immune responses. Furthermore, these mechanisms are likely to be nonredundant, in that a distinct suppressor mechanism most likely plays a prominent and identifiable role at a particular tissue and inflammatory setting.


Subject(s)
Inflammation Mediators/physiology , Interleukin-10/physiology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Animals , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Autoimmune Diseases/prevention & control , Colitis/genetics , Colitis/immunology , Colitis/prevention & control , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/physiology , Inflammation Mediators/metabolism , Integrases/genetics , Interleukin-10/deficiency , Interleukin-10/genetics , Luminescent Proteins/genetics , Lung/immunology , Lung/metabolism , Lung/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Organ Specificity/genetics , Organ Specificity/immunology , Skin/immunology , Skin/metabolism , Skin/pathology , T-Lymphocytes, Regulatory/pathology
3.
Am J Pathol ; 170(1): 188-202, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17200193

ABSTRACT

The impact of the local inflammatory response on the process of wound healing has been debated for decades. In particular, the question whether infiltrating macrophages and granulocytes promote or impede tissue repair has received much attention. In the present study, we show that wound healing is accelerated in mice deficient for the anti-inflammatory cytokine interleukin (IL)-10. IL-10-/- mice closed excisional wounds significantly earlier compared with IL-10-competent control littermates. This effect was attributable to accelerated epithelialization as well as enhanced contraction of the wound tissue in the mutant animals. Increased alpha-smooth muscle actin expression in IL-10-deficient mice suggests that augmented myofibroblast differentiation is responsible for the enhanced contraction of wounds in mutant mice. The number of macrophages infiltrating the wound tissue was significantly increased in IL-10-/- mice compared with control littermates suggesting that this cell type mediates the accelerated tissue repair. These results show for the first time that IL-10 can impede wound repair.


Subject(s)
Interleukin-10/deficiency , Wound Healing , Actins/biosynthesis , Animals , Cell Movement , Cell Proliferation , Cicatrix , Immunohistochemistry , Interleukin-10/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Neovascularization, Physiologic/genetics , Wound Healing/genetics
4.
Eur J Immunol ; 36(12): 3248-55, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17111348

ABSTRACT

Interleukin-10 (IL-10) is an important regulator of immune responses secreted by different cell types. We have previously shown that mice with selective inactivation of the IL-10 gene in T cells suffer from deregulated T cell responses similar to those observed in IL-10(-/-) animals. Unlike IL-10(-/-) mice, however, T cell-specific mutants do not mount an enhanced innate immune response to LPS, which must, therefore, be subject to control by IL-10 from non-T cells. Herein we show that subcutaneous injection of LPS, which causes moderate local inflammation in WT and T cell-specific IL-10 mutant mice, results in augmented inflammatory infiltration and extensive tissue necrosis in mice with deficiency for IL-10 in macrophages and neutrophils. Correspondingly, we observed an enhanced sensitivity of the macrophage/neutrophil-specific IL-10 mutants to systemic LPS exposure when compared with WT animals. In contrast, the inflammatory response of these mutants to CpG oligodeoxynucleotides was not different from that of WT mice. While IL-10(-/-) mice developed massive inflammation, necrosis and increased serum cytokine levels after subcutaneous CpG injection, only moderate responses were observed in macrophage/neutrophil-specific IL-10 mutant and WT mice. These results show that different innate immune responses can be subject to control by IL-10 from different cellular sources.


Subject(s)
Adjuvants, Immunologic/administration & dosage , CpG Islands/immunology , Inflammation Mediators/physiology , Interleukin-10/physiology , Lipopolysaccharides/immunology , Macrophages/immunology , Neutrophils/immunology , Oligodeoxyribonucleotides/immunology , Animals , Cells, Cultured , Inflammation Mediators/metabolism , Interleukin-10/deficiency , Interleukin-10/genetics , Lipopolysaccharides/administration & dosage , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Neutrophils/metabolism , Oligodeoxyribonucleotides/administration & dosage
5.
Arch Dermatol Res ; 298(4): 201-5, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16897075

ABSTRACT

Collagens in the extracellular matrix are thought to play an important role in regulating inflammatory responses by affecting cell adhesion and migration. The contact between collagens and cells is established mainly by alpha1beta1, alpha2beta1 and alpha11beta1integrin receptors. Here, we analyzed the contact hypersensitivity (CHS) reaction in mice that were genetically deficient in the collagen receptor alpha2beta1. Integrin alpha2beta1 is widely expressed and has been suggested to play an important role in mediating inflammatory responses. CHS was induced by applying dinitrofluorobenzene to abdominal skin and challenging with the same reagent on ear skin. Macroscopically and histologically, ear swelling in alpha2beta1-deficient mice did not differ from that in wild-type control mice. Immunohistological detection of infiltrated T lymphocytes, neutrophils and mast cells in inflamed ear skin revealed similar numbers in controls and integrin alpha2beta1-deficient animals. Our results suggest that the adhesive functions of integrin alpha2beta1 are dispensable for the CHS response; they may be compensated for by the collagen receptor alpha1beta1 or other collagen receptors.


Subject(s)
Dermatitis, Contact/immunology , Dermis/immunology , Integrin alpha2beta1/immunology , Animals , Extracellular Matrix/immunology , Histocytochemistry , Integrin alpha2beta1/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout
6.
J Exp Med ; 200(10): 1289-97, 2004 Nov 15.
Article in English | MEDLINE | ID: mdl-15534372

ABSTRACT

Interleukin (IL)-10 is a regulator of inflammatory responses and is secreted by a variety of different cell types including T cells. T regulatory cells have been shown to suppress immune responses by IL-10-dependent, but also IL-10-independent, mechanisms. Herein, we address the role of T cell-derived IL-10 in mice with an inactivation of the IL-10 gene restricted to T cells generated by Cre/loxP-mediated targeting of the IL-10 gene. Splenocytes from this T cell-specific mutant secrete increased amounts of proinflammatory cytokines after activation in vitro compared with show enhanced contact hypersensitivity reactions, and succumb to severe immunopathology upon infection with Toxoplasma gondii. Despite intact IL-10 genes in other cell types, the dysregulation of T cell responses observed in the T cell-specific IL-10 mutant closely resembles the phenotype in complete IL-10 deficiency. However, in contrast to complete IL-10 deficiency, sensitivity to endotoxic shock and irritant responses of the skin are not enhanced in the T cell-specific IL-10 mutant. Our data highlight the importance of T cell-derived IL-10 in the regulation of T cell responses and demonstrate that endotoxic shock and the irritant response of the skin are controlled by IL-10 from other cell types.


Subject(s)
Gene Silencing/immunology , Immunity, Cellular/immunology , Immunity, Innate/immunology , Interleukin-10/metabolism , T-Lymphocytes/metabolism , Animals , Histological Techniques , Interleukin-10/genetics , Intestinal Mucosa/pathology , Lipopolysaccharides/immunology , Mice , Mice, Transgenic , Mutagenesis, Insertional , Skin Irritancy Tests , Spleen/cytology , Spleen/metabolism , T-Lymphocytes/immunology , Toxoplasma/immunology
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