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Proc Natl Acad Sci U S A ; 114(31): E6400-E6409, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28698369


T-follicular helper (Tfh) cells differentiate through a multistep process, culminating in germinal center (GC) localized GC-Tfh cells that provide support to GC-B cells. T-follicular regulatory (Tfr) cells have critical roles in the control of Tfh cells and GC formation. Although Tfh-cell differentiation is inhibited by IL-2, regulatory T (Treg) cell differentiation and survival depend on it. Here, we describe a CD25- subpopulation within both murine and human PD1+CXCR5+Foxp3+ Tfr cells. It is preferentially located in the GC and can be clearly differentiated from CD25+ non-GC-Tfr, Tfh, and effector Treg (eTreg) cells by the expression of a wide range of molecules. In comparison to CD25+ Tfr and eTreg cells, CD25- Tfr cells partially down-regulate IL-2-dependent canonical Treg features, but retain suppressive function, while simultaneously up-regulating genes associated with Tfh and GC-Tfh cells. We suggest that, similar to Tfh cells, Tfr cells follow a differentiation pathway generating a mature GC-localized subpopulation, CD25- Tfr cells.

Centro Germinativo/citologia , Centro Germinativo/imunologia , Subunidade alfa de Receptor de Interleucina-2/genética , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Regulação para Baixo/imunologia , Fatores de Transcrição Forkhead/biossíntese , Humanos , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 1 de Ligação ao Domínio I Regulador Positivo/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Receptores CXCR5/biossíntese , Proteínas Repressoras/biossíntese
Nat Immunol ; 18(2): 173-183, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27992401


Most Foxp3+ regulatory T (Treg) cells develop in the thymus as a functionally mature T cell subpopulation specialized for immune suppression. Their cell fate appears to be determined before Foxp3 expression; yet molecular events that prime Foxp3- Treg precursor cells are largely obscure. We found that Treg cell-specific super-enhancers (Treg-SEs), which were associated with Foxp3 and other Treg cell signature genes, began to be activated in Treg precursor cells. T cell-specific deficiency of the genome organizer Satb1 impaired Treg-SE activation and the subsequent expression of Treg signature genes, causing severe autoimmunity due to Treg cell deficiency. These results suggest that Satb1-dependent Treg-SE activation is crucial for Treg cell lineage specification in the thymus and that its perturbation is causative of autoimmune and other immunological diseases.

Diferenciação Celular/imunologia , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Linfócitos T Reguladores/fisiologia , Ativação Transcricional/imunologia , Animais , Autoimunidade , Linhagem da Célula , Células Cultivadas , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Fatores de Transcrição Forkhead/genética , Tolerância Imunológica , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Especificidade de Órgãos , Células Precursoras de Linfócitos T/fisiologia
J Pharmacol Exp Ther ; 357(2): 258-63, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26945086


Although we previously demonstrated the contribution of the DP1receptor in nasal obstruction using animals sensitized with ovalbumin in the presence of adjuvant, the contribution of the DP1receptor in sneezing is unclear. Here, we developed a mouse model of Japanese cedar (JC:Cryptomeria japonica) pollinosis to evaluate the symptoms of sneezing. To achieve this, we used JC pollen crude extract in the absence of adjuvant to sensitize mice to develop a model closer to the pathophysiology of human JC pollinosis. The immunologic and pharmacologic features of this model are highly similar to those observed in JC pollinosis in humans. Using this model, we found that DP1receptor antagonists suppressed JC pollen extract-induced sneezing and that a DP1receptor agonist induced sneezing. Moreover, JC pollen extract-induced sneezing was diminished in DP1receptor knockout mice. In conclusion, we developed a novel mouse model of allergic rhinitis that closely mimics human JC pollinosis. A strong contribution of DP1receptor signaling to sneezing was demonstrated using this model, suggesting that DP1receptor antagonists could suppress sneezing and nasal obstruction, and therefore these agents could be a new therapeutic option for allergic rhinitis.

Antialérgicos/farmacologia , Cryptomeria/imunologia , Pólen/imunologia , Antagonistas de Prostaglandina/uso terapêutico , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Rinite Alérgica/fisiopatologia , Animais , Citocinas/biossíntese , Feminino , Imunoglobulina E/sangue , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Obstrução Nasal/etiologia , Obstrução Nasal/prevenção & controle , Extratos Vegetais , Receptores Imunológicos/genética , Receptores de Prostaglandina/genética , Espirro
J Biochem ; 159(3): 305-12, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26491063


Reelin is a secreted glycoprotein whose function is regulated by proteolysis. One of the specific cleavage sites of Reelin, called C-t, is located approximately between the sixth and seventh Reelin repeat but its exact site was unknown. We here show that a metalloprotease present in the culture supernatant of cerebellar granular neurons (CGN) cleaves Reelin between Ala2688 and Asp2689. A Reelin mutant in which Asp2689 is replaced by Lys (Reelin-DK) is resistant to C-t cleavage by culture supernatant of CGN. From biochemical characteristics and the cleavage site preference, meprin α and meprin ß were suggested candidate proteases and both were confirmed to cleave Reelin at the C-t site. Meprin α cleaved Reelin-DK but meprin ß did not. Actinonin, a meprin α and meprin ß inhibitor, did not inhibit the Reelin-cleaving activity of CGN and the amount of Reelin fragments in brains of meprin ß knock-out mice was not significantly different from that of the wild-type, indicating that meprin ß does not play a major role in Reelin cleavage under basal conditions. We propose that meprin α and meprin ß join the modulators of Reelin signalling as they cleave Reelin at a specific site and are upregulated under specific pathological conditions.

Moléculas de Adesão Celular Neuronais/metabolismo , Córtex Cerebral/citologia , Proteínas da Matriz Extracelular/metabolismo , Metaloendopeptidases/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/enzimologia , Proteólise , Serina Endopeptidases/metabolismo , Animais , Células COS , Técnicas de Cultura de Células , Cercopithecus aethiops , Células HEK293 , Humanos , Ácidos Hidroxâmicos/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Metaloendopeptidases/genética , Camundongos , Camundongos Knockout , Transdução de Sinais
Biochem Biophys Res Commun ; 417(3): 1014-7, 2012 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-22209789


Sphingomyelin (SM) plays important roles in regulating structure and function of plasma membrane, but how intracellular localization of SM is regulated in neuronal cells is not understood. Here we show that two isoforms of SM synthase (SMS) are differentially expressed in neuronal subtypes and that only SMS2 proteins localize in neurites of hippocampal neurons. Moreover, SMS proteins induce Lysenin-binding SM clusters exclusively in their vicinity although neurons hardly contain such cluster under control condition. These findings indicate three important notions about SM metabolism in neurons. First, the activity of SMS is the rate-limiting step of SM cluster formation. Second, the SM content or clustering can be modulated by SMS activity. Third, SMS1 and SMS2 play distinct roles in regulating local SM clustering. Particularly, SMS2, rather than SMS1, is likely to be the major enzyme that is important for SM synthesis in the long neurites and its tip, the growth cone.

Hipocampo/enzimologia , Neurônios/enzimologia , Esfingomielinas/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo , Animais , Células Cultivadas , Isoenzimas/metabolismo , Microdomínios da Membrana/enzimologia , Microdomínios da Membrana/metabolismo , Camundongos