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1.
Purinergic Signal ; 11(3): 317-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26059452

RESUMO

CD39/ENTPD1 is a prototypic member of the ectonucleoside triphosphate diphosphohydrolase (ENTPDase) family on cell surface. CD39 has been reported to be a marker of regulatory immune cells and catalyzes extracellular hydrolysis of nucleotides to generate AMP and, in tandem with CD73, adenosine. We have recently found in addition that co-expression of CD39 and CD161 by human CD4(+) T cells may become a biomarker of human Th17 cells. CD39 and CD161 have direct interactions that are further linked with acid sphingomyelinase (ASM). Upon activation of CD39 and CD161, the molecular interactions boost ASM bio-activity, which generates cellular ceramide to further mediate downstream signals inclusive of STAT3 and mTOR. We suggest modulation of human Th17 responsiveness by CD39 and CD161 and describe novel molecular mechanisms integrating elements of both extracellular nucleotide and sphingolipid homeostasis that are pivotal in the control of human Th17 cells and which could have therapeutic potential.


Assuntos
5'-Nucleotidase/metabolismo , Antígenos CD/genética , Antígenos CD/fisiologia , Apirase/genética , Apirase/fisiologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília B de Receptores Semelhantes a Lectina de Células NK/fisiologia , Células Th17/enzimologia , 5'-Nucleotidase/fisiologia , Animais , Humanos
2.
Blood ; 125(14): 2217-27, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25612621

RESUMO

NKR-P1B is a homodimeric type II transmembrane C-type lectinlike receptor that inhibits natural killer (NK) cell function upon interaction with its cognate C-type lectin-related ligand, Clr-b. The NKR-P1B:Clr-b interaction represents a major histocompatibility complex class I (MHC-I)-independent missing-self recognition system that monitors cellular Clr-b levels. We have generated NKR-P1B(B6)-deficient (Nkrp1b(-/-)) mice to study the role of NKR-P1B in NK cell development and function in vivo. NK cell inhibition by Clr-b is abolished in Nkrp1b(-/-) mice, confirming the inhibitory nature of NKR-P1B(B6). Inhibitory receptors also promote NK cell tolerance and responsiveness to stimulation; hence, NK cells expressing NKR-P1B(B6) and Ly49C/I display augmented responsiveness to activating signals vs NK cells expressing either or none of the receptors. In addition, Nkrp1b(-/-) mice are defective in rejecting cells lacking Clr-b, supporting a role for NKR-P1B(B6) in MHC-I-independent missing-self recognition of Clr-b in vivo. In contrast, MHC-I-dependent missing-self recognition is preserved in Nkrp1b(-/-) mice. Interestingly, spontaneous myc-induced B lymphoma cells may selectively use NKR-P1B:Clr-b interactions to escape immune surveillance by wild-type, but not Nkrp1b(-/-), NK cells. These data provide direct genetic evidence of a role for NKR-P1B in NK cell tolerance and MHC-I-independent missing-self recognition.


Assuntos
Imunidade Inata/imunologia , Células Matadoras Naturais/imunologia , Lectinas Tipo C/fisiologia , Linfoma de Células B/imunologia , Proteínas de Membrana/fisiologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/fisiologia , Animais , Western Blotting , Células Cultivadas , Feminino , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Ligantes , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
3.
J Immunol ; 188(10): 4980-91, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22491247

RESUMO

Innate immune recognition of virus-infected cells includes NK cell detection of changes to endogenous cell-surface proteins through inhibitory receptors. One such receptor system is the NK cell receptor protein-1B (NKR-P1B) and its ligand C-type lectin-related-b (Clr-b). NKR-P1B and Clr-b are encoded within the NK cell gene complex, a locus that has been linked to strain-dependent differences in susceptibility to infection by poxviruses. In this study, we report the impact of vaccinia virus (VV) and ectromelia virus infection on expression of Clr-b and Clr-b-mediated protection from NK cells. We observed a loss of Clr-b cell-surface protein upon VV and ectromelia virus infection of murine cell lines and bone marrow-derived macrophages. The reduction of Clr-b is more rapid than MHC class I, the prototypic ligand of NK cell inhibitory receptors. Reduction of Clr-b requires active viral infection but not expression of late viral genes, and loss of mRNA appears to lag behind loss of Clr-b surface protein. Clr-b-mediated protection from NK cells is lost following VV infection. Together, these results provide the second example of Clr-b modulation during viral infection and suggest reductions of Clr-b may be involved in sensitizing poxvirus-infected cells to NK cells.


Assuntos
Regulação para Baixo/imunologia , Células Matadoras Naturais/imunologia , Lectinas Tipo C/antagonistas & inibidores , Subfamília B de Receptores Semelhantes a Lectina de Células NK/fisiologia , Receptores Imunológicos/fisiologia , Vaccinia virus/imunologia , Vaccinia virus/metabolismo , Animais , Células CHO , Linhagem Celular , Linhagem Celular Tumoral , Cricetinae , Humanos , Hipersensibilidade/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/virologia , Lectinas Tipo C/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Transdução de Sinais/imunologia
4.
Cytokine Growth Factor Rev ; 21(6): 405-12, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21075040

RESUMO

Th17 cells are a recently discovered subset of T helper cells characterised by the release of IL-17, and are thought to be important for mobilization of immune responses against microbial pathogens, but which also contribute to the development of autoimmune diseases. The identification of C-type lectin receptors which are capable of regulating the balance between Th1 and Th17 responses has been of particular recent interest, which they control, in part, though the release of Th17 inducing cytokines. Many of these receptors recognise fungi, and other pathogens, and play key roles in driving the development of protective anti-microbial immunity. Here we will review the C-type lectins that have been linked to Th17 type responses and will briefly examine the role of Th17 responses in murine and human anti-fungal immunity.


Assuntos
Fungos/imunologia , Interleucina-17/imunologia , Lectinas Tipo C/imunologia , Células Th17/fisiologia , Animais , Células Apresentadoras de Antígenos/imunologia , Doenças Autoimunes/imunologia , Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Síndrome de Job/imunologia , Lectinas Tipo C/fisiologia , Receptor de Manose , Lectinas de Ligação a Manose/fisiologia , Proteínas de Membrana/fisiologia , Camundongos , Micoses/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/fisiologia , Receptores de Superfície Celular/fisiologia , Receptores de Reconhecimento de Padrão/fisiologia , Fatores de Transcrição/fisiologia , Proteína AIRE
5.
J Immunol ; 181(12): 8237-47, 2008 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19050240

RESUMO

IL-15 is an important cytokine involved in the survival and function of CD8(+) T cells and NK cells. IL-15 can be presented by IL-15Ralpha (IL-15RA) to bind with the shared IL-2/IL-15Rbeta and common gamma-chains, which activate signaling pathways on NK cells and CD8(+) T cells. In the present study, we characterized the function of trans-presented IL-15 on NK cells and CD8(+) T cells using TC-1 tumor cells transduced with a retrovirus encoding IL-15 linked to IL-15RA (IL-15/IL-15RA). We demonstrated that the expression of IL-15/IL-15RA on TC-1 cells led to increased percentages of tumor-infiltrating NK cells, NKT cells, and CD8(+) T cells, resulting in the inhibition of tumor growth in challenged mice. Additionally, in vivo Ab depletion experiments demonstrated that NK1.1(+) cells and CD8(+) T cells were important in this inhibition of tumor growth. Furthermore, this accumulation of immune cells and inhibition of tumor growth was abolished by a single amino acid mutation in the common gamma-chain binding site on IL-15. We also observed that IL-15/IL-15RA-transduced TC-1 cells led to the activation of STAT5 in NK and CD8(+) T cells in trans, which was abolished in the mutated IL-15/IL-15RA-transduced TC-1 cells. Taken together, our data suggest that common gamma-chain binding-dependent activation of the shared IL-15/IL-2Rbeta/common gamma signaling pathway may play an important role in the activation of NK cells and CD8(+) T cells, resulting in IL-15/IL-15RA trans-presentation-mediated inhibition of tumor growth.


Assuntos
Antígenos Ly/biossíntese , Linfócitos T CD8-Positivos/imunologia , Inibidores do Crescimento/fisiologia , Subunidade gama Comum de Receptores de Interleucina/fisiologia , Interleucina-15/fisiologia , Subunidade beta de Receptor de Interleucina-2/fisiologia , Células Matadoras Naturais/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/biossíntese , Neoplasias Ovarianas/prevenção & controle , Transdução de Sinais/imunologia , Animais , Apresentação de Antígeno/genética , Antígenos Ly/fisiologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Feminino , Inibidores do Crescimento/biossíntese , Subunidade gama Comum de Receptores de Interleucina/genética , Interleucina-15/biossíntese , Interleucina-15/genética , Interleucina-15/metabolismo , Subunidade alfa de Receptor de Interleucina-15/biossíntese , Subunidade alfa de Receptor de Interleucina-15/genética , Subunidade alfa de Receptor de Interleucina-15/metabolismo , Subunidade alfa de Receptor de Interleucina-15/fisiologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Subfamília B de Receptores Semelhantes a Lectina de Células NK/fisiologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/virologia , Retroviridae/genética , Transdução de Sinais/genética , Transdução Genética
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