Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
PLoS One ; 9(8): e105266, 2014.
Article in English | MEDLINE | ID: mdl-25121970

ABSTRACT

Dendritic cells (DC) presenting tumor antigens are crucial to induce potent T cell-mediated anti-tumor immune responses. Therefore DC-based cancer vaccines have been established for therapy, however clinical outcomes are often poor and need improvement. Using a mouse model of B16 melanoma, we found that the route of preventive DC vaccination critically determined tumor control. While repeated DC vaccination did not show an impact of the route of DC application on the prevention of tumor growth, a single DC vaccination revealed that both the imprinting of skin homing receptors and an enhanced proliferation state of effector T cells was seen only upon intracutaneous but not intravenous or intraperitoneal immunization. Tumor growth was prevented only by intracutaneous DC vaccination. Our results indicate that under suboptimal conditions the route of DC vaccination crucially determines the efficiency of tumor defense. DC-based strategies for immunotherapy of cancer should take into account the immunization route in order to optimize tissue targeting of tumor antigen specific T cells.


Subject(s)
Cancer Vaccines/immunology , Dendritic Cells/immunology , Immunization , Melanoma, Experimental/immunology , Adoptive Transfer , Animals , Antigens, Viral/genetics , Antigens, Viral/metabolism , Cancer Vaccines/administration & dosage , Cell Line, Tumor , Disease Models, Animal , Gene Expression , Glycoproteins/genetics , Glycoproteins/metabolism , Immunotherapy , Lymphocyte Activation/immunology , Melanoma, Experimental/pathology , Melanoma, Experimental/therapy , Mice , Mice, Transgenic , Peptide Fragments/genetics , Peptide Fragments/metabolism , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Receptors, Lymphocyte Homing/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Tumor Burden , Viral Proteins/genetics , Viral Proteins/metabolism
2.
J Exp Med ; 205(9): 2151-62, 2008 Sep 01.
Article in English | MEDLINE | ID: mdl-18725520

ABSTRACT

Allergic contact hypersensitivity (CHS) is a T cell-mediated inflammatory skin disease. Interleukin (IL)-12 is considered to be important in the generation of the allergen-specific T cell response. Loss of IL-12 function in IL-12Rbeta2-deficient mice, however, did not ameliorate the allergic immune response, suggesting alternate IL-12-independent pathways in the induction of CHS. Because exposure to contact allergens always takes place in the presence of microbial skin flora, we investigated the potential role of Toll-like receptors (TLRs) in the induction of CHS. Using mice deficient in TLR4, the receptor for bacterial lipopolysaccharide (LPS), IL-12 receptor (R) beta2, or both, we show that the concomitant absence of TLR4 and IL-12Rbeta2, but not the absence of TLR4 or IL-12Rbeta2 alone, prevented DC-mediated sensitization, generation of effector T cells, and the subsequent CHS response to 2,4,6-trinitro-1-chlorobenzene (TNCB), oxazolone, and fluorescein isothiocyanate. Introduction of the TLR4 transgene into the TLR4/IL-12Rbeta2 mutant restored the CHS inducibility, showing a requirement for TLR4 in IL-12-independent CHS induction. Furthermore, the concomitant absence of TLR2 and TLR4 prevented the induction of CHS to TNCB in IL-12-competent mice. Finally, CHS was inducible in germ-free wild-type and IL-12Rbeta2-deficient mice, but not in germ-free TLR4/IL-12Rbeta2 double deficient mice, suggesting that the necessary TLR activation may proceed via endogenous ligands.


Subject(s)
Dermatitis, Contact/immunology , Interleukin-12/metabolism , Toll-Like Receptors/metabolism , Allergens/chemistry , Animals , Cytokines/metabolism , Female , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Models, Biological , Signal Transduction , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 4/metabolism
3.
J Exp Med ; 205(7): 1559-65, 2008 Jul 07.
Article in English | MEDLINE | ID: mdl-18573908

ABSTRACT

Cutaneous immune responses must be tightly controlled to prevent unwanted inflammation in response to innocuous antigens, while maintaining the ability to combat skin-tropic pathogens. Foxp3(+) regulatory T (T reg) cells are potent immune regulators and are found at high frequency in both human and mouse skin. Although T reg cells migrate to the skin and can dampen immune responses during experimentally induced inflammation or infection, the importance of cutaneous T reg cells for maintaining normal immune homeostasis in the skin has not been addressed. To selectively block T reg cell function in the skin, we restored the T reg cell compartment in Foxp3-deficient scurfy mice with cells whose ability to migrate to the skin was impaired because of targeted mutation of alpha-1,3-fucosyltransferase VII (Fut7). Although Fut7-deficient T reg cells were present at normal frequency and could function in all other tissues examined, these animals rapidly developed severe cutaneous inflammation. Thus, skin-resident T reg cell are essential for maintaining normal immune homeostasis at this site.


Subject(s)
Cell Movement/immunology , Forkhead Transcription Factors , Fucosyltransferases/immunology , Homeostasis/immunology , Skin/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Cell Movement/genetics , Dermatitis/enzymology , Dermatitis/genetics , Dermatitis/immunology , Fucosyltransferases/genetics , Fucosyltransferases/metabolism , Homeostasis/genetics , Humans , Mice , Mice, Knockout , Mutation , Skin/enzymology , Skin/pathology , T-Lymphocytes, Regulatory/enzymology
4.
Eur J Immunol ; 35(4): 1056-65, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15739162

ABSTRACT

Tissue-selective homing is established during naive T cell activation by the tissue microenvironment and tissue-specific dendritic cells (DC). The factors driving induction and maintenance of T cell homing patterns are still largely unknown. Here we show that soluble factors produced during the interaction of T cells with CD11c(+) DC isolated from skin- or small intestine-associated tissues differentially modulate expression of the corresponding tissue-selective homing receptors (E-selectin ligands and alpha4beta7 integrin/CCR9, respectively) on murine CD8(+) T cells. Injection of tissue-specific DC via different routes induces T cells with homing receptors characteristic of the corresponding local tissue microenvironment, independent of the origin of the DC. These data indicate an important role for signals delivered in trans. Moreover, DC can reprogram the homing receptor expression on T cells previously polarized in vitro for homing to skin or small intestine. Importantly, skin-homing memory T cells stimulated directly ex vivo can also be reprogrammed by intestinal DC to a gut-homing phenotype. Our results show that tissue-selective homing receptor expression on effector and memory T cells is governed by inductive as well as suppressive signals from both DC and tissue microenvironments.


Subject(s)
Dendritic Cells/immunology , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/immunology , Animals , Bone Marrow Cells/immunology , Integrin alpha4/immunology , Integrin beta Chains/immunology , Mice
5.
J Immunol ; 173(5): 3178-85, 2004 Sep 01.
Article in English | MEDLINE | ID: mdl-15322178

ABSTRACT

One of the unusual properties of chemically reactive haptens is their capacity to simultaneously generate immunogenic determinants for hapten-specific CD8(+) and CD4(+) T cells. Surprisingly, however, a clear dominance of CD8(+) effector T cells is observed in murine contact hypersensitivity to various haptens and upon T cell priming with hapten-modified APCs in vitro. In this study we show that trinitrophenyl-specific CD8(+) T cells actively prevent CD4(+) T cell priming in vitro. This process requires cell-cell contact and is dependent on the expression of Fas on the CD4(+) T cells. Our results reveal an important Fas-dependent mechanism for the regulation of hapten-specific CD4(+) T cell responses by CD8(+) T cells, which causes the dominance of CD8(+) effector T cells and the active suppression of a CD4(+) T cell response. Moreover, our demonstration of reduced contact hypersensitivity to trinitrophenyl in the absence of Fas, but not of perforin and/or granzymes A and B, underlines the important role of Fas as a pathogenetic factor for contact hypersensitivity.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Proteins/physiology , Receptors, Tumor Necrosis Factor , Trinitrobenzenes/immunology , Animals , Apoptosis/immunology , CD4-Positive T-Lymphocytes/physiology , CD8-Positive T-Lymphocytes/physiology , Dermatitis, Contact/immunology , Granzymes , Interferon-gamma/metabolism , Mice , Mice, Knockout , Proteins/genetics , Proteins/immunology , Serine Endopeptidases/deficiency , Serine Endopeptidases/genetics , fas Receptor
SELECTION OF CITATIONS
SEARCH DETAIL
...