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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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MEDLINE

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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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MEDLINE

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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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