Your browser doesn't support javascript.
loading
Montrer: 20 | 50 | 100
Résultats 1 - 6 de 6
Filtrer
Plus de filtres










Base de données
Gamme d'année
1.
Proc Natl Acad Sci U S A ; 111(6): 2067-74, 2014 Feb 11.
Article de Anglais | MEDLINE | ID: mdl-24520172

RÉSUMÉ

The NDFIP1 (neural precursor cell expressed, developmentally down-regulated protein 4 family-interacting protein 1) adapter for the ubiquitin ligase ITCH is genetically linked to human allergic and autoimmune disease, but the cellular mechanism by which these proteins enable foreign and self-antigens to be tolerated is unresolved. Here, we use two unique mouse strains--an Ndfip1-YFP reporter and an Ndfip1-deficient strain--to show that Ndfip1 is progressively induced during T-cell differentiation and activation in vivo and that its deficiency causes a cell-autonomous, Forkhead box P3-independent failure of peripheral CD4(+) T-cell tolerance to self and exogenous antigen. In small cohorts of antigen-specific CD4(+) cells responding in vivo, Ndfip1 was necessary for tolerogen-reactive T cells to exit cell cycle after one to five divisions and to abort Th2 effector differentiation, defining a step in peripheral tolerance that provides insights into the phenomenon of T-cell anergy in vivo and is distinct from the better understood process of Bcl2-interacting mediator of cell death-mediated apoptosis. Ndfip1 deficiency precipitated autoimmune pancreatic destruction and diabetes; however, this depended on a further accumulation of nontolerant anti-self T cells from strong stimulation by exogenous tolerogen. These findings illuminate a peripheral tolerance checkpoint that aborts T-cell clonal expansion against allergens and autoantigens and demonstrate how hypersensitive responses to environmental antigens may trigger autoimmunity.


Sujet(s)
Adaptation physiologique , Lymphocytes T CD4+/immunologie , Protéines de transport/physiologie , Cycle cellulaire , Protéines membranaires/physiologie , Animaux , Lymphocytes T CD4+/cytologie , Différenciation cellulaire , Prolifération cellulaire , Facteurs de transcription Forkhead/métabolisme , Protéines et peptides de signalisation intercellulaire , Activation des lymphocytes , Souris , Souris de lignée C57BL
2.
Proc Natl Acad Sci U S A ; 103(35): 13132-7, 2006 Aug 29.
Article de Anglais | MEDLINE | ID: mdl-16916931

RÉSUMÉ

The A2A adenosine receptor (A2AR) has been shown to be a critical and nonredundant negative regulator of immune cells in protecting normal tissues from inflammatory damage. We hypothesized that A2AR also protects cancerous tissues by inhibiting incoming antitumor T lymphocytes. Here we confirm this hypothesis by showing that genetic deletion of A2AR in the host resulted in rejection of established immunogenic tumors in approximately 60% of A2AR-deficient mice with no rejection observed in control WT mice. The use of antagonists, including caffeine, or targeting the A2 receptors by siRNA pretreatment of T cells improved the inhibition of tumor growth, destruction of metastases, and prevention of neovascularization by antitumor T cells. The data suggest that effects of A2AR are T cell autonomous. The inhibition of antitumor T cells via their A2AR in the adenosine-rich tumor microenvironment may explain the paradoxical coexistence of tumors and antitumor immune cells in some cancer patients (the "Hellstrom paradox"). We propose to target the hypoxia-->adenosine-->A2AR pathway as a cancer immunotherapy strategy to prevent the inhibition of antitumor T cells in the tumor microenvironment. The same strategy may prevent the premature termination of immune response and improve the vaccine-induced development of antitumor and antiviral T cells. The observations of autoimmunity during melanoma rejection in A2AR-deficient mice suggest that A2AR in T cells is also important in preventing autoimmunity. Thus, although using the hypoxia-->adenosine-->A2AR pathway inhibitors may improve antitumor immunity, the recruitment of this pathway by selective drugs is expected to attenuate the autoimmune tissue damage.


Sujet(s)
Lymphocytes T CD8+/immunologie , Mélanome/immunologie , Mélanome/métabolisme , Récepteur A2A à l'adénosine/métabolisme , Adénosine/métabolisme , Antagonistes des récepteurs A2 à l'adénosine , Animaux , Thérapie cellulaire et tissulaire , Humains , Immunothérapie adoptive , Interféron gamma/biosynthèse , Mélanome/anatomopathologie , Souris , Souris de lignée BALB C , Souris de lignée C57BL , Mutation/génétique , Récepteur A2A à l'adénosine/déficit
3.
J Immunol ; 174(1): 90-8, 2005 Jan 01.
Article de Anglais | MEDLINE | ID: mdl-15611231

RÉSUMÉ

Dendritic cell (DC)-based vaccination represents a promising approach to harness the specificity and potency of the immune system to combat cancer. Finding optimal strategies for tumor Ag preparation and subsequent pulsing of DC, as well as improving the immunogenicity of weak tumor Ags remain among the first challenges of this approach. In this report, we use a prophylactic vaccine consisting of DC loaded with whole, nonmanipulated B16-F10 melanoma cells that had been stressed by heat shock and gamma irradiation. Stressed B16-F10 cells underwent apoptosis and were internalized by bone marrow-derived DC during coculture. Surprisingly, coculture of DC with stressed B16-F10 undergoing apoptosis and necrosis did not induce DC maturation. However, a marked retardation in tumor growth was observed in C57BL/6 mice immunized using DC loaded with stressed B16-F10 cells and subsequently challenged with B16-F10 cells. Growth retardation was further increased by treating DC with LPS before in vivo administration. In vivo depletion studies revealed that both CD8(+) and CD4(+) T cells played a critical role in retarding tumor growth. In addition, treatment with anti-CD25 Ab to deplete CD4(+)CD25(+) regulatory T cells before DC vaccination considerably improved the effect of the vaccine and allowed the development of long-lived immune responses that were tumor protective. Our results demonstrate that depletion of regulatory T cells is an effective approach to improving the success of DC-based vaccination against weakly immunogenic tumors. Such a strategy can be readily applied to other tumor models and extended to therapeutic vaccination settings.


Sujet(s)
Lymphocytes T CD4+/immunologie , Vaccins anticancéreux/immunologie , Cellules dendritiques/immunologie , Mélanome expérimental/prévention et contrôle , Stress physiologique , Animaux , Lymphocytes T CD8+/immunologie , Mort cellulaire/physiologie , Techniques de coculture , Cellules dendritiques/cytologie , Cytométrie en flux , Rayons gamma , Température élevée , Souris , Récepteurs à l'interleukine-2/immunologie , Cellules cancéreuses en culture
4.
Eur J Immunol ; 33(8): 2074-82, 2003 Aug.
Article de Anglais | MEDLINE | ID: mdl-12884280

RÉSUMÉ

We used 5-(and 6-) carboxyfluorescein diacetate succinimidyl ester labeled TCR-transgenic CD4(+) T cells to investigate the contribution of B7 costimulation to T cell activation and clonal expansion. B7 costimulation was blocked with the fusion protein cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)-Ig, which prevents the interaction of B7 with its receptor CD28 on T cells. CTLA4-Ig had different effects depending on the density of antigen (Ag)/MHC ligands available by T cells. In the presence of CTLA4-Ig, tenfold higher concentrations of Ag were required for T cells to undergo cell division in vitro. At high Ag concentrations, T cell division occurred at comparable rates whether in the presence or absence of CTLA4-Ig; however, T cell survival and clonal expansion were strongly inhibited. Addition of IL-2 restored T cell survival but not responsiveness to low doses of Ag. In vivo, B7 costimulation was similarly required for the survival of Ag-specific T cells but not for cell division in response to high amounts of Ag. Thus, B7 costimulation regulates CD4(+) T cell responses by promoting cell division in the presence of limiting amounts of Ag, and by protecting T cells from the onset of apoptosis.


Sujet(s)
Antigènes CD/métabolisme , Antigène CD80/métabolisme , Lymphocytes T CD4+/cytologie , Lymphocytes T CD4+/immunologie , Glycoprotéines membranaires/métabolisme , Abatacept , Transfert adoptif , Animaux , Antigènes/administration et posologie , Antigène CD86 , Lymphocytes T CD4+/effets des médicaments et des substances chimiques , Division cellulaire/effets des médicaments et des substances chimiques , Survie cellulaire/effets des médicaments et des substances chimiques , Cytochromes de type c/immunologie , Immunoconjugués/pharmacologie , Techniques in vitro , Activation des lymphocytes/effets des médicaments et des substances chimiques , Souris , Souris transgéniques , Fragments peptidiques/immunologie , Récepteurs aux antigènes des cellules T/génétique , Protéines de fusion recombinantes/pharmacologie , Thymidine/métabolisme
5.
Int Immunol ; 14(6): 677-84, 2002 Jun.
Article de Anglais | MEDLINE | ID: mdl-12039919

RÉSUMÉ

Genes outside the MHC create a general susceptibility to autoimmunity in non-obese diabetic (NOD) mice. Here we describe marked differences in dendritic cell generation in vivo, caused by non-MHC NOD genes. Analyses of splenic dendritic cells from the autoimmunity-prone NOD.H-2(k) mice revealed a relative over-representation of the CD8 alpha(-) subsets, in contrast to the level of these subsets observed in the autoimmunity-resistant B10.H-2(k) congenic strain or other H-2(k) strains. The imbalance towards CD8 alpha(-) dendritic cells was selectively manifested by NOD.H-2(k)-derived cells in radiation chimeras reconstituted with equal mixtures of NOD.H-2(k) and B10.H-2(k) bone marrow cells. In addition to the cell-intrinsic imbalance in dendritic cell subsets, the myeloid lineage overall was intrinsically altered by NOD genes, as this lineage was disproportionately derived from the NOD.H-2(k) donor in mixed chimeras. These results identify a striking effect of non-MHC NOD genes upon the balance of dendritic cell subsets that may contribute to the generalized defects in self-tolerance in the NOD strain.


Sujet(s)
Cellules dendritiques/immunologie , Diabète de type 1/génétique , Diabète de type 1/immunologie , Animaux , Auto-immunité , Antigènes CD8/métabolisme , Cellules dendritiques/classification , Antigènes H-2/génétique , Cellules souches hématopoïétiques/immunologie , Souris , Souris congéniques , Souris de lignée AKR , Souris de lignée BALB C , Souris de lignée CBA , Souris de lignée NOD , Chimère post-radique/génétique , Chimère post-radique/immunologie , Autotolérance
6.
Immunol Cell Biol ; 80(2): 198-206, 2002 Apr.
Article de Anglais | MEDLINE | ID: mdl-11940121

RÉSUMÉ

Genes outside the MHC create a general susceptibility to autoimmunity in non-obese diabetic (NOD) mice. In this study, we describe marked differences in dendritic cell generation, in vitro, caused by non-MHC NOD genes. Bone marrow cells from NOD.H-2k mice cultured in vitro with GM-CSF and IL-4 generated a reduced yield of dendritic cells when compared to bone marrow cells from B10.H-2k mice. This was due to failure to pass through successive rounds of cell division and elevated levels of apoptosis in NOD.H-2k precursor cells. This aberrant response to GM-CSF and IL-4 was unique to the NOD.H-2k background when compared to bone marrow cells from other H-2k congenic strains, and coculture experiments showed that it was cell-autonomous. Overall, the results described in this study demonstrate a striking effect of non-MHC NOD genes on dendritic cell generation from myeloid precursors derived from the NOD.H-2k strain. These results identify a useful genetic model to explore the regulation of dendritic cell formation. Conceivably, the dysregulation of the dendritic cell system described here may contribute to the generalized defects in self-tolerance in the NOD strain.


Sujet(s)
Cellules dendritiques/immunologie , Diabète de type 1/génétique , Animaux , Cellules de la moelle osseuse/composition chimique , Cellules de la moelle osseuse/effets des médicaments et des substances chimiques , Cellules de la moelle osseuse/immunologie , Différenciation cellulaire/effets des médicaments et des substances chimiques , Cellules cultivées , Diabète de type 1/immunologie , Gènes MHC de classe II , Facteur de stimulation des colonies de granulocytes et de macrophages/pharmacologie , Interleukine-4/pharmacologie , Souris , Souris de lignée AKR , Souris de lignée BALB C , Souris de lignée CBA , Souris de lignée NOD , Obésité/génétique
SÉLECTION CITATIONS
DÉTAIL DE RECHERCHE
...