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[PMID]:28814605
[Au] Autor:Lownik JC; Luker AJ; Damle SR; Cooley LF; El Sayed R; Hutloff A; Pitzalis C; Martin RK; El Shikh MEM; Conrad DH
[Ad] Endereço:Center for Clinical and Translational Research, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
[Ti] Título:ADAM10-Mediated ICOS Ligand Shedding on B Cells Is Necessary for Proper T Cell ICOS Regulation and T Follicular Helper Responses.
[So] Source:J Immunol;199(7):2305-2315, 2017 Oct 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The proper regulation of ICOS and ICOS ligand (ICOSL) has been shown to be essential for maintaining proper immune homeostasis. Loss of either protein results in defective humoral immunity, and overexpression of ICOS results in aberrant Ab production resembling lupus. How ICOSL is regulated in response to ICOS interaction is still unclear. We demonstrate that a disintegrin and metalloproteinase (ADAM)10 is the primary physiological sheddase of ICOSL in mice and humans. Using an in vivo system in which ADAM10 is deleted only on B cells, elevated levels of ICOSL were seen. This increase is also seen when ADAM10 is deleted from human B cell lines. Identification of the primary sheddase has allowed the characterization of a novel mechanism of ICOS regulation. In wild-type mice, interaction of ICOS/ICOSL results in ADAM10-induced shedding of ICOSL on B cells and moderate ICOS internalization on T cells. When this shedding is blocked, excessive ICOS internalization occurs. This results in severe defects in T follicular helper development and T 2 polarization, as seen in a house dust mite exposure model. In addition, enhanced T 1 and T 17 immune responses are seen in experimental autoimmune encephalomyelitis. Blockade of ICOSL rescues T cell ICOS surface expression and rescues, at least in part, T follicular helper numbers and the abnormal Ab production previously reported in these mice. Overall, we propose a novel regulation of the ICOS/ICOSL axis, with ADAM10 playing a direct role in regulating ICOSL, as well as indirectly regulating ICOS, thus controlling ICOS/ICOSL-dependent responses.
[Mh] Termos MeSH primário: Linfócitos B/imunologia
Regulação da Expressão Gênica
Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo
Linfócitos T Auxiliares-Indutores/imunologia
Linfócitos T Reguladores/imunologia
[Mh] Termos MeSH secundário: Proteína ADAM10/deficiência
Proteína ADAM10/genética
Proteína ADAM10/metabolismo
Secretases da Proteína Precursora do Amiloide/deficiência
Secretases da Proteína Precursora do Amiloide/genética
Secretases da Proteína Precursora do Amiloide/metabolismo
Animais
Modelos Animais de Doenças
Encefalomielite Autoimune Experimental/imunologia
Homeostase
Seres Humanos
Ligante Coestimulador de Linfócitos T Induzíveis/genética
Ligante Coestimulador de Linfócitos T Induzíveis/imunologia
Proteínas de Membrana/deficiência
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Camundongos
Pyroglyphidae/imunologia
Células Th1/imunologia
Células Th17/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ICOSLG protein, human); 0 (Icosl protein, mouse); 0 (Inducible T-Cell Co-Stimulator Ligand); 0 (Membrane Proteins); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.4.24.81 (ADAM10 Protein); EC 3.4.24.81 (ADAM10 protein, human); EC 3.4.24.81 (Adam10 protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700833


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[PMID]:28605013
[Au] Autor:Sacquin A; Gador M; Fazilleau N
[Ad] Endereço:Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
[Ti] Título:The strength of BCR signaling shapes terminal development of follicular helper T cells in mice.
[So] Source:Eur J Immunol;47(8):1295-1304, 2017 Aug.
[Is] ISSN:1521-4141
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Antibody production is key for effective immune response and relies on follicular helper T (Tfh) cells. B cell-Tfh cell interactions result either in an extra-follicular low affinity B-cell response or in germinal center reactions producing high-affinity memory B cells and long-lived plasma cells. As Tfh cells influence B-cell commitment, it also became clear that B cells influence these interactions in ways that still remain unresolved. We observed that strong BCR signals decreased Tfh-cell differentiation in vitro, which correlated with decreased expression of ICOS-L at the surface of stimulated B cells. Further, we comprehensively demonstrated that ICOS-L expression correlated with the level of Tfh differentiation irrespective of antigen presentation at the surface of activated B cells. Our in vivo experiments could show that immunization with a high-affinity antigen for B cells resulted in much less Tfh development than immunization with low-affinity antigen. Furthermore, blocking ICOS-L in vivo inhibited Tfh development when using low-affinity antigen. Altogether, these results indicate that BCR affinity shapes Tfh-cell development in part through ICOS/ICOS-L interactions. Ultimately, we reveal new depths in the B cell-Tfh cell crosstalk that could eventually result in better vaccine protocols.
[Mh] Termos MeSH primário: Linfócitos B/imunologia
Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo
Ativação Linfocitária
Receptores de Antígenos de Linfócitos B/metabolismo
Subpopulações de Linfócitos T/imunologia
Linfócitos T Auxiliares-Indutores/imunologia
[Mh] Termos MeSH secundário: Animais
Apresentação do Antígeno
Linfócitos B/metabolismo
Diferenciação Celular
Citometria de Fluxo
Centro Germinativo/imunologia
Ligante Coestimulador de Linfócitos T Induzíveis/genética
Camundongos
Receptores de Antígenos de Linfócitos B/imunologia
Receptores CXCR5/genética
Receptores CXCR5/imunologia
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Icosl protein, mouse); 0 (Inducible T-Cell Co-Stimulator Ligand); 0 (Receptors, Antigen, B-Cell); 0 (Receptors, CXCR5)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE
[do] DOI:10.1002/eji.201746952


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[PMID]:28330898
[Au] Autor:Tyler CJ; McCarthy NE; Lindsay JO; Stagg AJ; Moser B; Eberl M
[Ad] Endereço:Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
[Ti] Título:Antigen-Presenting Human γδ T Cells Promote Intestinal CD4 T Cell Expression of IL-22 and Mucosal Release of Calprotectin.
[So] Source:J Immunol;198(9):3417-3425, 2017 May 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The cytokine IL-22 plays a critical role in mucosal barrier defense, but the mechanisms that promote IL-22 expression in the human intestine remain poorly understood. As human microbe-responsive Vγ9/Vδ2 T cells are abundant in the gut and recognize microbiota-associated metabolites, we assessed their potential to induce IL-22 expression by intestinal CD4 T cells. Vγ9/Vδ2 T cells with characteristics of APCs were generated from human blood and intestinal organ cultures, then cocultured with naive and memory CD4 T cells obtained from human blood or the colon. The potency of blood and intestinal γδ T-APCs was compared with that of monocytes and dendritic cells, by assessing CD4 T cell phenotypes and proliferation as well as cytokine and transcription factor profiles. Vγ9/Vδ2 T cells in human blood, colon, and terminal ileum acquired APC functions upon microbial activation in the presence of microenvironmental signals including IL-15, and were capable of polarizing both blood and colonic CD4 T cells toward distinct effector fates. Unlike monocytes or dendritic cells, gut-homing γδ T-APCs employed an IL-6 independent mechanism to stimulate CD4 T cell expression of IL-22 without upregulating IL-17. In human intestinal organ cultures, microbial activation of Vγ9/Vδ2 T cells promoted mucosal secretion of IL-22 and ICOSL/TNF-α-dependent release of the IL-22 inducible antimicrobial protein calprotectin without modulating IL-17 expression. In conclusion, human γδ T-APCs stimulate CD4 T cell responses distinct from those induced by myeloid APCs to promote local barrier defense via mucosal release of IL-22 and calprotectin. Targeting of γδ T-APC functions may lead to the development of novel gut-directed immunotherapies and vaccines.
[Mh] Termos MeSH primário: Linfócitos T CD4-Positivos/imunologia
Colo/imunologia
Imunoterapia/métodos
Interleucinas/metabolismo
Mucosa Intestinal/imunologia
Complexo Antígeno L1 Leucocitário/metabolismo
Receptores de Antígenos de Linfócitos T gama-delta/metabolismo
[Mh] Termos MeSH secundário: Apresentação do Antígeno
Células Cultivadas
Técnicas de Cocultura
Seres Humanos
Memória Imunológica
Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo
Interleucina-15/imunologia
Interleucina-6/metabolismo
Interleucinas/genética
Lipopolissacarídeos/imunologia
Ativação Linfocitária
Fator de Necrose Tumoral alfa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ICOSLG protein, human); 0 (Inducible T-Cell Co-Stimulator Ligand); 0 (Interleukin-15); 0 (Interleukin-6); 0 (Interleukins); 0 (Leukocyte L1 Antigen Complex); 0 (Lipopolysaccharides); 0 (Receptors, Antigen, T-Cell, gamma-delta); 0 (Tumor Necrosis Factor-alpha); 0 (interleukin-22)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700003


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[PMID]:28179539
[Au] Autor:Ammitzbøll C; Börnsen L; Romme Christensen J; Ratzer R; Romme Nielsen B; Søndergaard HB; von Essen MR; Sellebjerg F
[Ad] Endereço:Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark cecilie.ammitzboell@regionh.dk.
[Ti] Título:Smoking reduces circulating CD26 CD161 MAIT cells in healthy individuals and patients with multiple sclerosis.
[So] Source:J Leukoc Biol;101(5):1211-1220, 2017 May.
[Is] ISSN:1938-3673
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Upon chronic cigarette smoke exposure, inhaled antigens and irritants cause altered lung immune homeostasis. Circulating immune cells are affected, and smoking is associated with an increased risk of developing various disorders, including multiple sclerosis (MS). This study was conducted to determine the impact of smoking on circulating immune cell subsets. Furthermore, we determined whether any smoking-associated changes were related to MS. With the use of flow cytometry, CFSE assays, and ELISpot assays, we analyzed circulating immune cell phenotypes and quantified antigen-induced proliferation and cytokine secretion in smokers and nonsmokers in a cohort of 100 healthy individuals (HI). In addition, we analyzed immune cell subsets associated with smoking in 2 independent cohorts of patients with MS. In HI smokers compared with nonsmokers, we found increased blood cell counts of granulocytes, monocytes, and lymphocytes. These cells were not more proinflammatory, autoreactive, or EBV reactive compared with cells from nonsmokers. Phenotypic differences were seen in plasmacytoid dendritic cells (pDCs) and CD8 T cells as higher percentages of ICOS ligand (ICOSL) pDCs and lower percentages of CD26 CD161 CD8 T cells and CCR6 CD8 T cells in smokers compared with nonsmokers. In supplemental analyses, we showed that CD26 CD161 CD8 T cells were mainly mucosal-associated invariant T cells (MAITs). Comparable frequencies of ICOSL pDCs, CCR6 CD8 T cells, and CD26 CD161 CD8 T cells were found between HI and MS patients who were nonsmokers. Our findings suggest general proinflammatory effects from smoking combined with skewing of specific cell populations in HI and MS patients. The function of these cell populations needs further investigation.
[Mh] Termos MeSH primário: Linfócitos T CD8-Positivos/efeitos dos fármacos
Dipeptidil Peptidase 4/imunologia
Esclerose Múltipla/imunologia
Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia
Fumar/imunologia
[Mh] Termos MeSH secundário: Adulto
Linfócitos T CD8-Positivos/imunologia
Linfócitos T CD8-Positivos/patologia
Contagem de Células
Estudos de Coortes
Cotinina/sangue
Cotinina/farmacologia
Células Dendríticas/efeitos dos fármacos
Células Dendríticas/imunologia
Células Dendríticas/patologia
Dipeptidil Peptidase 4/genética
Feminino
Regulação da Expressão Gênica/imunologia
Granulócitos/efeitos dos fármacos
Granulócitos/imunologia
Granulócitos/patologia
Seres Humanos
Imunofenotipagem
Ligante Coestimulador de Linfócitos T Induzíveis/genética
Ligante Coestimulador de Linfócitos T Induzíveis/imunologia
Masculino
Meia-Idade
Monócitos/efeitos dos fármacos
Monócitos/imunologia
Monócitos/patologia
Esclerose Múltipla/etiologia
Esclerose Múltipla/genética
Esclerose Múltipla/patologia
Subfamília B de Receptores Semelhantes a Lectina de Células NK/genética
Cultura Primária de Células
Fumar/efeitos adversos
Fumar/genética
Fumar/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ICOSLG protein, human); 0 (Inducible T-Cell Co-Stimulator Ligand); 0 (KLRB1 protein, human); 0 (NK Cell Lectin-Like Receptor Subfamily B); EC 3.4.14.5 (DPP4 protein, human); EC 3.4.14.5 (Dipeptidyl Peptidase 4); K5161X06LL (Cotinine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE
[do] DOI:10.1189/jlb.3A0616-267R


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[PMID]:28002569
[Au] Autor:Kunishige T; Taniguchi H; Terada M; Akiba H; Yagita H; Abe R; Hori J
[Ad] Endereço:Department of Ophthalmology, Nippon Medical School, Tokyo, Japan.
[Ti] Título:Protective Role of ICOS and ICOS Ligand in Corneal Transplantation and in Maintenance of Immune Privilege.
[So] Source:Invest Ophthalmol Vis Sci;57(15):6815-6823, 2016 Dec 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: The interaction between the inducible costimulatory molecule (ICOS) and ICOS ligand (ICOSL) has been implicated in the differentiation and functions of T cells. The purpose of the present study was to determine the role of ICOS-ICOSL in the immune privilege of corneal allografts. Methods: Expression of ICOS and ICOSL mRNA from mouse eyes was assessed by RT-PCR. Corneas of C57BL/6 mice were orthotopically transplanted into the eyes of ICOS-/- BALB/c recipients and BALB/c wild-type (WT) recipients treated with anti-ICOSL mAb, and graft survival was assessed. A separate set of WT and ICOS-/- BALB/c mice received an anterior chamber injection of C57BL/6 splenocytes, and induction of allospecific anterior chamber-associated immune deviation (ACAID) was assessed. In vitro, cornea was incubated with T cells from WT and ICOS-/- BALB/c mice, and destruction of corneal endothelial cells (CECs) and the population of Foxp3+ CD25+ CD4+ T cells was assessed. Results: Inducible costimulatory molecule ligand mRNA was constitutively expressed in the cornea, iris-ciliary body, and retina. Allograft survival in ICOS-/- recipients and WT recipients treated with anti-ICOSL mAb was significantly shorter than in control recipients. Anterior chamber-associated immune deviation was induced less efficiently in ICOS-/- mice. Destruction of CECs by alloreactive ICOS-/- T cells was enhanced compared with WT T cells. After coincubation with allogeneic corneal tissue, the proportion of regulatory T cells was significantly greater among WT T cells than in ICOS-/- T cells. Conclusions: The expression of ICOSL in the cornea and the ICOS-mediated induction of Foxp3+ CD4+ regulatory T cells may contribute to successful corneal allograft survival.
[Mh] Termos MeSH primário: Córnea/metabolismo
Transplante de Córnea
Regulação da Expressão Gênica
Sobrevivência de Enxerto/imunologia
Imunidade Celular
Ligante Coestimulador de Linfócitos T Induzíveis/genética
Proteína Coestimuladora de Linfócitos T Induzíveis/genética
[Mh] Termos MeSH secundário: Animais
Córnea/imunologia
Córnea/patologia
Citometria de Fluxo
Rejeição de Enxerto/genética
Rejeição de Enxerto/imunologia
Ligante Coestimulador de Linfócitos T Induzíveis/biossíntese
Proteína Coestimuladora de Linfócitos T Induzíveis/biossíntese
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C3H
Camundongos Endogâmicos C57BL
RNA Mensageiro/genética
Reação em Cadeia da Polimerase em Tempo Real
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Linfócitos T Reguladores/imunologia
Transplante Homólogo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Icos protein, mouse); 0 (Icosl protein, mouse); 0 (Inducible T-Cell Co-Stimulator Ligand); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (RNA, Messenger)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170615
[Lr] Data última revisão:
170615
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161222
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.16-20644


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[PMID]:27798154
[Au] Autor:Gigliotti CL; Boggio E; Clemente N; Shivakumar Y; Toth E; Sblattero D; D'Amelio P; Isaia GC; Dianzani C; Yagi J; Rojo JM; Chiocchetti A; Boldorini R; Bosetti M; Dianzani U
[Ad] Endereço:Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
[Ti] Título:ICOS-Ligand Triggering Impairs Osteoclast Differentiation and Function In Vitro and In Vivo.
[So] Source:J Immunol;197(10):3905-3916, 2016 Nov 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Osteoblasts, osteocytes, and osteoclasts (OCs) are involved in the bone production and resorption, which are crucial in bone homeostasis. OC hyperactivation plays a role in the exaggerated bone resorption of diseases such as osteoporosis, rheumatoid arthritis, and osteolytic tumor metastases. This work stems from the finding that OCs can express B7h (ICOS-Ligand), which is the ligand of the ICOS T cell costimulatory molecule. Because recent reports have shown that, in endothelial, dendritic, and tumor cells, B7h triggering modulates several activities of these cells, we analyzed the effect of B7h triggering by recombinant ICOS-Fc on OC differentiation and function. The results showed that ICOS-Fc inhibits RANKL-mediated differentiation of human monocyte-derived OC-like cells (MDOCs) by inhibiting the acquirement of the OC morphology, the CD14 cathepsin K phenotype, and the expression of tartrate-resistant acid phosphatase, OSCAR, NFATc1, and DC-STAMP. Moreover, ICOS-Fc induces a reversible decrease in the sizes of cells and nuclei and cathepsin K expression in mature MDOCs. Finally, ICOS-Fc inhibits the osteolytic activities of MDOCs in vitro and the development of bone loss in ovariectomized or soluble RANKL-treated mice. These findings open a novel field in the pharmacological use of agonists and antagonists of the ICOS-B7h system.
[Mh] Termos MeSH primário: Diferenciação Celular
Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo
Osteoclastos/fisiologia
[Mh] Termos MeSH secundário: Animais
Movimento Celular
Células Cultivadas
Seres Humanos
Ligante Coestimulador de Linfócitos T Induzíveis/genética
Ligante Coestimulador de Linfócitos T Induzíveis/imunologia
Ligante Coestimulador de Linfócitos T Induzíveis/farmacologia
Proteína Coestimuladora de Linfócitos T Induzíveis/genética
Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo
Glicoproteínas de Membrana/genética
Glicoproteínas de Membrana/metabolismo
Camundongos
Monócitos/imunologia
Monócitos/fisiologia
Osteoclastos/efeitos dos fármacos
Osteoclastos/imunologia
Engenharia de Proteínas
Ligante RANK/antagonistas & inibidores
Ligante RANK/metabolismo
Receptor Ativador de Fator Nuclear kappa-B/metabolismo
Receptores Fc/genética
Receptores Fc/imunologia
Proteínas Recombinantes de Fusão/farmacologia
Fosfatase Ácida Resistente a Tartarato/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ICOSLG protein, human); 0 (Icosl protein, mouse); 0 (Inducible T-Cell Co-Stimulator Ligand); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (Membrane Glycoproteins); 0 (RANK Ligand); 0 (Receptor Activator of Nuclear Factor-kappa B); 0 (Receptors, Fc); 0 (Recombinant Fusion Proteins); EC 3.1.3.2 (ACP5 protein, human); EC 3.1.3.2 (Tartrate-Resistant Acid Phosphatase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161106
[St] Status:MEDLINE


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[PMID]:27560832
[Au] Autor:Schenk H; Neumann D; Kloth C
[Ad] Endereço:a Institute of Pharmacology, Hannover Medical School , Hannover , Germany ;
[Ti] Título:Histamine regulates murine primary dendritic cell functions.
[So] Source:Immunopharmacol Immunotoxicol;38(5):379-84, 2016 Oct.
[Is] ISSN:1532-2513
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE AND DESIGN: The modulation of antigen uptake and activation of dendritic cells (DCs) by histamine may function as a regulator of inflammation. Therefore, we sought to determine the impact of histamine on antigen uptake by and activation of murine DCs. MATERIAL AND METHODS: DCs from spleen and lung were either identified by flow cytometry or were immunomagnetically enriched. Cells were stimulated with histamine, and the regulation of MHC-II and co-stimulatory molecule expression (CD80, CD86, and ICOS-L) and antigen uptake were quantified by flow cytometry. Individual contributions of the histamine receptor subtypes were determined by using the antagonists mepyramine (histamine H1-receptor: H1R), famotidine (H2R), and JNJ 7777120 (H4R). RESULTS: Histamine accelerated the uptake of soluble antigen via the H1R, H2R, and H4R in splenic DCs. Co-stimulatory molecule expression was enhanced already by enrichment procedures, thus, the analyses were performed in unseparated cell populations. Histamine enhanced the expression of CD86 and ICOS-L while expression of CD80 was unaffected. Antagonism at H1R, H2R, and H4R and at H1R and H4R reduced the histamine-induced enhanced expression of CD86 and ICOS-L, respectively. CONCLUSIONS: Histamine contributes to the regulation of the immunological synapse by stimulation of antigen uptake and activation of DCs via H1R, H2R, and H4R.
[Mh] Termos MeSH primário: Células Dendríticas/imunologia
Histamina/farmacologia
Sinapses Imunológicas/imunologia
[Mh] Termos MeSH secundário: Animais
Antígeno B7-1/imunologia
Antígeno B7-2/imunologia
Células Cultivadas
Células Dendríticas/citologia
Ligante Coestimulador de Linfócitos T Induzíveis/imunologia
Camundongos
Receptores Histamínicos H1/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (B7-1 Antigen); 0 (B7-2 Antigen); 0 (Cd86 protein, mouse); 0 (Icosl protein, mouse); 0 (Inducible T-Cell Co-Stimulator Ligand); 0 (Receptors, Histamine H1); 820484N8I3 (Histamine)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160826
[St] Status:MEDLINE
[do] DOI:10.1080/08923973.2016.1214144


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[PMID]:27246829
[Au] Autor:Le KS; Thibult ML; Just-Landi S; Pastor S; Gondois-Rey F; Granjeaud S; Broussais F; Bouabdallah R; Colisson R; Caux C; Ménétrier-Caux C; Leroux D; Xerri L; Olive D
[Ad] Endereço:Centre de recherche en Cancérologie de Marseille, Inserm U1068/CNRS U7258, Marseille, France. Aix Marseille Université, Marseille, France.
[Ti] Título:Follicular B Lymphomas Generate Regulatory T Cells via the ICOS/ICOSL Pathway and Are Susceptible to Treatment by Anti-ICOS/ICOSL Therapy.
[So] Source:Cancer Res;76(16):4648-60, 2016 Aug 15.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The prognosis of follicular lymphoma (FL) patients is suspected to be influenced by tumor-infiltrating regulatory T cells (Treg). The mechanism of Treg enrichment in FL and their impact on malignant FL B cells remains to be elucidated. We analyzed 46 fresh lymph node biopsy samples, including FL (n = 20), diffuse large B-cell lymphoma (n = 10), classical Hodgkin lymphoma (n = 9), and reactive lymphadenitis (n = 7). Using multicolor flow cytometry and cell sorting, we observed an accumulation of CD25(high)CD127(low/neg) Tregs in FL tissues. These Tregs comprised activated ICOS(+) Tregs that were able to suppress not only conventional T cells, but also FL B cells. These FL B cells were able to express ICOSL in vitro and to generate CD25(high)FoxP3(high) Tregs expressing ICOS. Treg generation was associated with ICOS/ICOSL engagement and was abrogated by antagonist anti-ICOS and anti-ICOSL antibodies. Interactions between Tregs and FL B cells resulted in ICOSL downregulation on FL B cells. Our results highlight a key role for Tregs in FL pathogenesis and suggest that targeting the ICOS/ICOSL pathway may be a promising immunotherapy for FL treatment. Cancer Res; 76(16); 4648-60. ©2016 AACR.
[Mh] Termos MeSH primário: Ligante Coestimulador de Linfócitos T Induzíveis/imunologia
Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia
Linfócitos do Interstício Tumoral/imunologia
Linfoma de Células B/imunologia
Linfócitos T Reguladores/imunologia
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/farmacologia
Antineoplásicos/farmacologia
Separação Celular
Citometria de Fluxo
Seres Humanos
Imuno-Histoquímica
Ligante Coestimulador de Linfócitos T Induzíveis/antagonistas & inibidores
Proteína Coestimuladora de Linfócitos T Induzíveis/antagonistas & inibidores
Camundongos
Reação em Cadeia da Polimerase
Transdução de Sinais/imunologia
Linfócitos T Reguladores/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antineoplastic Agents); 0 (ICOS protein, human); 0 (ICOSLG protein, human); 0 (Inducible T-Cell Co-Stimulator Ligand); 0 (Inducible T-Cell Co-Stimulator Protein)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170721
[Lr] Data última revisão:
170721
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160602
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-15-0589


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[PMID]:27197182
[Au] Autor:Metzger TC; Long H; Potluri S; Pertel T; Bailey-Bucktrout SL; Lin JC; Fu T; Sharma P; Allison JP; Feldman RM
[Ad] Endereço:Rinat Laboratories, Pfizer Inc., South San Francisco, California. Todd.Metzger@pfizer.com Reid.Feldman@pfizer.com.
[Ti] Título:ICOS Promotes the Function of CD4+ Effector T Cells during Anti-OX40-Mediated Tumor Rejection.
[So] Source:Cancer Res;76(13):3684-9, 2016 07 01.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ICOS is a T-cell coregulatory receptor that provides a costimulatory signal to T cells during antigen-mediated activation. Antitumor immunity can be improved by ICOS-targeting therapies, but their mechanism of action remains unclear. Here, we define the role of ICOS signaling in antitumor immunity using a blocking, nondepleting antibody against ICOS ligand (ICOS-L). ICOS signaling provided critical support for the effector function of CD4(+) Foxp3(-) T cells during anti-OX40-driven tumor immune responses. By itself, ICOS-L blockade reduced accumulation of intratumoral T regulatory cells (Treg), but it was insufficient to substantially inhibit tumor growth. Furthermore, it did not impede antitumor responses mediated by anti-4-1BB-driven CD8(+) T cells. We found that anti-OX40 efficacy, which is based on Treg depletion and to a large degree on CD4(+) effector T cell (Teff) responses, was impaired with ICOS-L blockade. In contrast, the provision of additional ICOS signaling through direct ICOS-L expression by tumor cells enhanced tumor rejection and survival when administered along with anti-OX40 therapy. Taken together, our results showed that ICOS signaling during antitumor responses acts on both Teff and Treg cells, which have opposing roles in promoting immune activation. Thus, effective therapies targeting the ICOS pathway should seek to promote ICOS signaling specifically in effector CD4(+) T cells by combining ICOS agonism and Treg depletion. Cancer Res; 76(13); 3684-9. ©2016 AACR.
[Mh] Termos MeSH primário: Adenocarcinoma/imunologia
Linfócitos T CD8-Positivos/imunologia
Neoplasias Colorretais/imunologia
Receptores OX40/metabolismo
Linfócitos T Reguladores/imunologia
[Mh] Termos MeSH secundário: Adenocarcinoma/metabolismo
Adenocarcinoma/prevenção & controle
Animais
Neoplasias Colorretais/metabolismo
Neoplasias Colorretais/prevenção & controle
Citocinas/metabolismo
Feminino
Citometria de Fluxo
Seres Humanos
Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo
Ativação Linfocitária
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Nus
Receptores de Antígenos de Linfócitos T
Transdução de Sinais
Células Tumorais Cultivadas
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytokines); 0 (ICOSLG protein, human); 0 (Inducible T-Cell Co-Stimulator Ligand); 0 (Receptors, Antigen, T-Cell); 0 (Receptors, OX40)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160520
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-15-3412


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[PMID]:27183569
[Au] Autor:Smith C; Buhlmann JE; Wang X; Bartlett A; Lim B; Barrington RA
[Ad] Endereço:Department of Microbiology and Immunology, University of South Alabama, Mobile, AL 36688; and.
[Ti] Título:CD275-Independent IL-17-Producing T Follicular Helper-like Cells in Lymphopenic Autoimmune-Prone Mice.
[So] Source:J Immunol;196(12):4935-46, 2016 Jun 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:T cells undergo homeostatic expansion and acquire an activated phenotype in lymphopenic microenvironments. Restoration of normal lymphocyte numbers typically re-establishes normal homeostasis, and proinflammatory cytokine production returns to baseline. Mice deficient in guanine nucleotide exchange factor RasGRP1 exhibit dysregulated homeostatic expansion, which manifests as lymphoproliferative disease with autoantibody production. Our previous work revealed that autoreactive B cells lacking RasGRP1 break tolerance early during development, as well as during germinal center responses, suggesting that T cell-independent and T cell-dependent mechanisms are responsible. Examination of whether a particular T cell subset is involved in the breach of B cell tolerance revealed increased Th17 cells in Rasgrp1-deficient mice relative to control mice. Rasgrp1-deficient mice lacking IL-17R had fewer germinal centers, and germinal centers that formed contained fewer autoreactive B cells, suggesting that IL-17 signaling is required for a break in B cell tolerance in germinal centers. Interestingly, a fraction of Th17 cells from Rasgrp1-deficient mice were CXCR5(+) and upregulated levels of CD278 coordinate with their appearance in germinal centers, all attributes of T follicular helper cells (Tfh17). To determine whether CD278-CD275 interactions were required for the development of Tfh17 cells and for autoantibody, Rasgrp1-deficient mice were crossed with CD275-deficient mice. Surprisingly, mice deficient in RasGRP1 and CD275 formed Tfh17 cells and germinal centers and produced similar titers of autoantibodies as mice deficient in only RasGRP1. Therefore, these studies suggest that requirements for Tfh cell development change in lymphopenia-associated autoimmune settings.
[Mh] Termos MeSH primário: Autoimunidade
Centro Germinativo/imunologia
Ligante Coestimulador de Linfócitos T Induzíveis/imunologia
Interleucina-17/imunologia
Linfopenia/imunologia
Linfócitos T Auxiliares-Indutores/imunologia
[Mh] Termos MeSH secundário: Animais
Autoanticorpos/biossíntese
Autoanticorpos/imunologia
Linfócitos B/imunologia
Centro Germinativo/citologia
Fatores de Troca do Nucleotídeo Guanina/deficiência
Homeostase
Tolerância Imunológica/genética
Ligante Coestimulador de Linfócitos T Induzíveis/deficiência
Proteína Coestimuladora de Linfócitos T Induzíveis/genética
Interleucina-17/biossíntese
Camundongos
Receptores CXCR5/genética
Receptores de Interleucina-17/deficiência
Transdução de Sinais
Células Th17/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantibodies); 0 (Blr1 protein, mouse); 0 (Guanine Nucleotide Exchange Factors); 0 (Il17r protein, mouse); 0 (Inducible T-Cell Co-Stimulator Ligand); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (Interleukin-17); 0 (Rasgrp1 protein, mouse); 0 (Receptors, CXCR5); 0 (Receptors, Interleukin-17)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160517
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1402193



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