th17-inflammation-model-oropharyngeal-candidiasis-immunodeficient

Th17 Inflammation Model of Oropharyngeal Candidiasis in Immunodeficient Mice

Oropharyngeal Candidiasis (OPC) disease is caused not only due to the lack of host immune resistance, but also the absence of appropriate regulation of ...

Case Western Reserve University

Survival of antigen-experienced T cells is essential for the generation of adaptive immune responses. Here, we show that the genetic and antibody-mediated inactivation of CD152 (cytotoxic T lymphocyte antigen 4) in T helper (Th) effector cells reduced the frequency of nonapoptotic cells in a completely Fas/Fas ligand (FasL)-dependent manner. CD152 cross-linking together with stimulation of CD3 and CD28 on activated Th2 cells prevented activation-induced cell death (AICD) as a result of reduced Fas and FasL expression. Apoptosis protection conferred by CD152 correlated with the up-regulation of Bcl-2 and was mediated by phosphatidylinositol 3 kinase, which prevented FasL expression through the inhibitory phosphorylation of Forkhead transcription factor FKHRL1. We show that signals induced by CD152 act directly on activated T lymphocytes and, due to its differential surface expression on activated Th1 and Th2 cells, induce resistance to AICD mainly in Th2 cells.

CD152 (CTLA-4) determines the unequal resistance of Th1 and Th2 cells against activation-induced cell death by a mechanism requiring PI3 kinase function.

Astrocytes are the first cells that are encountered by T cells invading the central nervous system (CNS) by crossing the blood-brain barrier. We show that primary astrocytes contribute to the immune privilege of the CNS by suppressing Th1 and Th2 cell activation, proliferation and effector function. Moreover, this astrocyte-mediated inhibition of Th effector cells was effective on already activated, proliferating cells. Transforming growth factor (TGF)-beta secreted by astrocytes or T cells was not the major factor in the inhibition. The inhibition of T-cell proliferation induced by astrocytes was mainly mediated by upregulation of CTLA-4 on already activated T cells, which occurred both with and without cell-cell contact. Upregulation of the inhibitory molecule CTLA-4 on autoreactive Th cells, as mediated by astrocytes, thus represents a novel mechanism for securing the immune privilege of the CNS.

Astrocytes protect the CNS: antigen-specific T helper cell responses are inhibited by astrocyte-induced upregulation of CTLA-4 (CD152).

CD8 T cell expansion and cytokine production is needed to generate an effective defense against viral invasion of the host. These features of CD8 T lymphocytes are regulated, especially during primary responses, by positive and negative costimulation. We show in this study that surface expression of CD152 is highly up-regulated on activated CD8 T lymphocytes during primary immune responses, suggesting a prominent regulatory role. Indeed, production of the proinflammatory cytokine IFN-gamma, but not TNF-alpha, by CD8 T cells was inhibited by CD152 engagement. The inhibition was regulated independent of proliferation and IL-2 production, but dependent on the quality of the TCR signaling. We show that signals induced by CD152 on activated CD8 T lymphocytes reduce the frequency of IFN-gamma(high)-expressing cells. Our data also show that in activated CD8 T cells, the CD152-mediated inhibition of cytokine production is more pronounced than inhibition of their proliferation.

High IFN-gamma production of individual CD8 T lymphocytes is controlled by CD152 (CTLA-4).

A key issue in mammalian immunology is how CD4+CD25+Foxp3+ regulatory T cells (T(reg) cells) suppress immune responses. Here we show that T(reg) cells induced apoptosis of effector CD4+ T cells in vitro and in vivo in a mouse model of inflammatory bowel disease. T(reg) cells did not affect the early activation or proliferation of effector CD4+ T cells. Cytokines that signal through the common gamma-chain suppressed T(reg) cell-induced apoptosis. T(reg) cell-induced effector CD4+ T cell death required the proapoptotic protein Bim, and effector CD4+ T cells incubated with T(reg) cells showed less activation of the prosurvival kinase Akt and less phosphorylation of the proapoptotic protein Bad. Thus, cytokine deprivation-induced apoptosis is a prominent mechanism by which T(reg) cells inhibit effector T cell responses.

CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells.

CD4+CD25+Foxp3+ regulatory T (Treg) cells are believed to play an important role in suppressing autoimmunity and maintaining peripheral tolerance. How their survival is regulated in the periphery is less clear. Here we show that Treg cells express receptors for gamma chain cytokines and are dependent on an exogenous supply of these cytokines to overcome cytokine withdrawal apoptosis in vitro. This result was validated in vivo by the accumulation of Treg cells in Bim-/- and Bcl-2 tg mice which have arrested cytokine deprivation apoptosis. We also found that CD25 and Foxp3 expression were down-regulated in the absence of these cytokines. CD25+ cells from Scurfy mice do not depend on cytokines for survival demonstrating that Foxp3 increases their dependence on cytokines by suppressing cytokine production in Treg cells. Our study reveals that the survival of Treg cells is strictly dependent on cytokines and cytokine producing cells because they do not produce cytokines. Our study thus, demonstrates that different gamma chain cytokines regulate Treg homeostasis in the periphery by differentially regulating survival and proliferation. These findings may shed light on ways to manipulate Treg cells that could be utilized for their therapeutic applications.

The control of CD4+CD25+Foxp3+ regulatory T cell survival.

Controlled expansion and contraction of lymphocytes both during and after an adaptive immune response are imperative to sustain a healthy immune system. Both extrinsic and intrinsic pathways of lymphocyte apoptosis are programmed to eliminate cells at the proper time to ensure immune homeostasis. Genetic disorders of apoptosis described in mice and humans have established Fas and Bim as critical pro-apoptotic molecules responsible for T-cell death in response to T-cell receptor restimulation and cytokine withdrawal, respectively. Emerging evidence prompts revision of this classic paradigm, especially for our understanding of restimulation-induced cell death (RICD) and its physiological purpose. Recent work indicates that RICD employs both Fas and Bim for T-cell deletion, dispelling the notion that these molecules are assigned to mutually exclusive apoptotic pathways. Furthermore, new mouse model data combined with our discovery of defective RICD in X-linked lymphoproliferative disease (XLP) patient T cells suggest that RICD is essential for precluding excess T-cell accumulation and associated immunopathology during the course of certain infections. Here, we review how these advances offer a refreshing new perspective on the phenomenon of T-cell apoptosis induced through antigen restimulation, including its relevance to immune homeostasis and potential for therapeutic interventions.

The power and the promise of restimulation-induced cell death in human immune diseases.

Th17 cells and CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells are thought to promote and suppress inflammatory responses, respectively. Here we explore why under Th17 cell polarizing conditions, Treg cells did not suppress, but rather upregulated, the expression of interleukin-17A (IL-17A), IL-17F, and IL-22 from responding CD4(+) T cells (Tresp cells). Upregulation of IL-17 cytokines in Tresp cells was dependent on consumption of IL-2 by Treg cells, especially at early time points both in vitro and in vivo. During an oral Candida albicans infection in mice, Treg cells induced IL-17 cytokines in Tresp cells, which markedly enhanced fungal clearance and recovery from infection. These findings show how Treg cells can promote acute Th17 cell responses to suppress mucosal fungus infections and reveal that Treg cells have a powerful capability to fight infections besides their role in maintaining tolerance or immune homeostasis.

CD4(+)CD25(+)Foxp3(+) regulatory T cells promote Th17 cells in vitro and enhance host resistance in mouse Candida albicans Th17 cell infection model.

Notch &#x4FE1;&#x53F7;&#x662F;&#x9002;&#x5F53;&#x955C;&#x5934;&#x53D1;&#x5C55;&#x7684;&#x5FC5;&#x8981;&#x6761;&#x4EF6;&#xFF0C;&#x4F46;&#x662F;&#x6CA1;&#x6709;&#x8C03;&#x67E5;&#x4E2A;&#x522B;&#x69FD;&#x53E3;&#x53D7;&#x4F53;&#x7684;&#x5177;&#x4F53;&#x8981;&#x6C42;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x62A5;&#x544A; Notch2 &#x6761;&#x4EF6;&#x7A81;&#x53D8;&#x5C0F;&#x9F20;&#x8868;&#x73B0;&#x51FA;&#x4E25;&#x91CD;&#x7684;&#x5C0F;&#x773C;&#x7403;&#x81F4;&#x75C5;&#xFF0C;&#x51CF;&#x5C11;&#x77B3;&#x5B54;&#x5F00;&#x53E3;&#xFF0C;&#x7834;&#x574F;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x5F62;&#x6001;&#xFF0C;&#x6700;&#x7EC8;&#x635F;&#x5931;&#x7684;&#x524D;&#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#x3001; &#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x53D1;&#x80B2;&#x4E0D;&#x5168;&#x3001; &#x51C0;&#x5316;&#x5DE5;&#x827A;&#x7F3A;&#x9677;&#x548C;&#x767D;&#x5185;&#x969C;&#x6676;&#x4F53;&#x8868;&#x578B;&#x3002;Notch2 &#x7A81;&#x53D8;&#x4F53; E14.5 &#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x8F66;&#x53A2;&#x8FD8;&#x6301;&#x7EED;&#x955C;&#x5934;&#x79F8;&#x79C6;&#x5C3D;&#x65E9; E11.5&#xFF0C;&#x4EE5;&#x53CA;&#x5F02;&#x5E38; DNA &#x5408;&#x6210;&#x3002;&#x57FA;&#x56E0;&#x8868;&#x8FBE;&#x5206;&#x6790;&#x663E;&#x793A;&#x540E;&#x7684; Notch2 &#x7684;&#x635F;&#x5931;&#xFF0C;&#x6709;&#x6C34;&#x5E73;&#x7684;&#x5347;&#x9AD8; Cdkn1a &#x7EC6;&#x80DE;&#x5468;&#x671F;&#x8C03;&#x8282;&#x56E0;&#x5B50;&#x7684; (p21Cip1)&#x3001; Ccnd2 (CyclinD2) &#x548C; Trp63 (p63) &#x7684;&#x6D88;&#x6781;&#x8C03;&#x8282; Wnt &#x4FE1;&#x53F7;&#xFF0C;&#x518D;&#x52A0;&#x4E0A;&#x4E0B;&#x8C03; Cdh1 (E-&#x9499;&#x7C98;&#x86CB;&#x767D;)&#x3002;Notch2 &#x53BB;&#x9664;&#x8FD8;&#x5BFC;&#x81F4;&#x6BD4;&#x4F8B;&#x589E;&#x52A0;&#x7684;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#xFF0C;&#x5982;&#x5728; Rbpj &#x548C; Jag1 &#x6761;&#x4EF6;&#x7A81;&#x53D8;&#x955C;&#x5934;&#x88AB;&#x53D1;&#x73B0;&#x3002;&#x7136;&#x800C;&#xFF0C;Notch2 &#x4E0D;&#x9700;&#x8981;&#x673A;&#x573A;&#x5FEB;&#x7EBF;&#x6269;&#x6563;&#xFF0C;&#x8868;&#x660E;&#x4E0D;&#x540C;&#x7684;&#x53D7;&#x4F53;&#x8C03;&#x8282;&#x8FD9;&#x4E00;&#x8FC7;&#x7A0B;&#x3002;&#x6211;&#x4EEC;&#x53D1;&#x73B0; Notch2 &#x901A;&#x5E38;&#x963B;&#x6B62;&#x955C;&#x5934;&#x7956;&#x7EC6;&#x80DE;&#x6B7B;&#x4EA1;&#x3002;&#x603B;&#x4F53;&#x800C;&#x8A00;&#xFF0C;&#x6211;&#x4EEC;&#x5F97;&#x51FA;&#x7ED3;&#x8BBA; Notch2 &#x4ECB;&#x5BFC;&#x7684;&#x4FE1;&#x53F7;&#x8F6C;&#x5BFC;&#x8C03;&#x8282;&#x955C;&#x5934;&#x5F62;&#x6001;&#x3001; &#x7EC6;&#x80DE;&#x51CB;&#x4EA1;&#x3001; &#x7EC6;&#x80DE;&#x5468;&#x671F;&#x64A4;&#x51FA;&#x548C;&#x4E8C;&#x6B21;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x5206;&#x5316;&#x3002;

Notch2 &#x53D7;&#x4F53;&#x5728;&#x773C;&#x955C;&#x5934;&#x7684;&#x6761;&#x4EF6;&#x6D88;&#x878D;&#x3002;

Notch signaling is essential for proper lens development, however the specific requirements of individual Notch receptors have not been investigated. Here we report the lens phenotypes of Notch2 conditionally mutant mice, which exhibited severe microphthalmia, reduced pupillary openings, disrupted fiber cell morphology, eventual loss of the anterior epithelium, fiber cell dysgenesis, denucleation defects, and cataracts. Notch2 mutants also had persistent lens stalks as early as E11.5, and aberrant DNA synthesis in the fiber cell compartment by E14.5. Gene expression analyses showed that upon loss of Notch2, there were elevated levels of the cell cycle regulators Cdkn1a (p21Cip1), Ccnd2 (CyclinD2), and Trp63 (p63) that negatively regulates Wnt signaling, plus down-regulation of Cdh1 (E-Cadherin). Removal of Notch2 also resulted in an increased proportion of fiber cells, as was found in Rbpj and Jag1 conditional mutant lenses. However, Notch2 is not required for AEL proliferation, suggesting that a different receptor regulates this process. We found that Notch2 normally blocks lens progenitor cell death. Overall, we conclude that Notch2-mediated signaling regulates lens morphogenesis, apoptosis, cell cycle withdrawal, and secondary fiber cell differentiation.

Conditional ablation of the Notch2 receptor in the ocular lens.

Signalisation Notch est essentiel pour le d&#xE9;veloppement lentille correcte, mais les exigences sp&#xE9;cifiques de r&#xE9;cepteurs Notch individuels n&#x26;#39;ont pas &#xE9;t&#xE9; investigu&#xE9;s. Ici, nous rapportons les ph&#xE9;notypes de lentilles de NOTCH2 souris mutantes conditionnellement, qui pr&#xE9;sentaient microphtalmie s&#xE9;v&#xE8;re, la r&#xE9;duction des ouvertures pupillaires, perturb&#xE9; la morphologie des cellules de fibres, de la perte &#xE9;ventuelle de l&#x26;#39;&#xE9;pith&#xE9;lium, dysg&#xE9;n&#xE9;sie ant&#xE9;rieure cellule de fibres, de d&#xE9;fauts denucleation et les cataractes. NOTCH2 mutants &#xE9;galement eu tiges de lentilles persistants que d&#xE8;s E11.5, et la synth&#xE8;se d&#x26;#39;ADN aberrant dans le compartiment de la cellule de fibres par E14.5. Analyses d&#x26;#39;expression g&#xE9;nique ont montr&#xE9; que lors de la perte de Notch2, il y avait des niveaux &#xE9;lev&#xE9;s de la r&#xE9;glementation du cycle cellulaire CDKN1A (p21Cip1), Ccnd2 (CyclinD2), et Trp63 (p63) qui r&#xE9;gule n&#xE9;gativement la signalisation Wnt, ainsi que la r&#xE9;gulation n&#xE9;gative de Cdh1 (E-cadh&#xE9;rine ). Enl&#xE8;vement des Notch2 &#xE9;galement donn&#xE9; lieu &#xE0; une proportion accrue de cellules fibreuses, comme on l&#x26;#39;a trouv&#xE9; dans Rbpj et JAG1 conditionnelles lentilles mutantes. Toutefois, Notch2 n&#x26;#39;est pas requise pour la prolif&#xE9;ration AEL, ce qui sugg&#xE8;re que un r&#xE9;cepteur diff&#xE9;rent r&#xE9;glemente ce processus. Nous avons constat&#xE9; que Notch2 normalement lentille blocs anc&#xEA;tre mort cellulaire. Dans l&#x26;#39;ensemble, nous concluons que Notch2 la signalisation m&#xE9;di&#xE9;e par r&#xE9;glemente la morphogen&#xE8;se objectif, l&#x26;#39;apoptose, le retrait du cycle cellulaire, la diff&#xE9;renciation cellulaire et secondaire de la fibre.

Ablation conditionnelle du r&#xE9;cepteur Notch2 dans la lentille oculaire

Kerbe Signalisierung unbedingt richtige Objektiv-Entwicklung, jedoch nicht die spezifischen Anforderungen der einzelnen Notch Rezeptoren untersucht haben. Hier berichten wir &uuml;ber die Objektiv-Ph&auml;notypen Notch2 bedingt Mutante M&auml;use, die schweren Mikrophthalmie ausgestellt, Pupillen &Ouml;ffnungen reduziert, gest&ouml;rt Faser Zellmorphologie, letztendlichen Verlust der vorderen Epithel Faser Zelle Dysgenesie, Denucleation M&auml;ngel, und Katarakte. Notch2 Mutanten hatte auch persistente Objektiv Stiele bereits als E11.5 und aberrante DNA-Synthese in der Faser Zelle Fach von E14.5. Gen Ausdruck Analysen nachwiesen, dass beim Ausfall der Notch2, erh&ouml;hte Niveaus der Zellzyklus Regulatoren Cdkn1a (p21Cip1), Ccnd2 (CyclinD2), und Trp63 (p63) reguliert, die negativ Wnt signalisieren, zuz&uuml;glich Herunterregulation Cdh1 (E-Cadherin). Entfernung von Notch2 f&uuml;hrte ebenfalls einen erh&ouml;hten Anteil an Ballaststoffen Zellen, wie in Rbpj und Jag1 bedingte mutant Objektive gefunden wurde. Ist jedoch Notch2 nicht erforderlich f&uuml;r die Vermehrung von AEL, was darauf hindeutet, dass ein anderes Rezeptor dieser Prozess regelt. Wir fanden, dass Notch2 normalerweise Objektiv Stammvater Zelltod blockiert. Insgesamt schlie&szlig;en wir, dass Notch2-vermittelte Signalisierung Objektiv Morphogenese, Apoptosis, Zellzyklus R&uuml;ckzug und sekund&auml;ren Faser Zelldifferenzierung regelt.

Bedingte Ablation des Notch2-Rezeptors in der okul&auml;re Linse.

Tacca di segnalazione &egrave; essenziale per lo sviluppo obiettivo corretto, tuttavia non sono state indagate le esigenze specifiche dei singoli recettori Notch. Qui riportiamo i fenotipi lente di Notch2 topi condizionalmente mutanti, che esposto microftalmia severa, ridotto aperture pupillare, sconvolto la morfologia cellulare fibra, eventuale perdita del epitelio anteriore, disgenesia cella fibra, denucleation difetti e cataratta. Notch2 mutanti avevano anche persistenti lente gambi gi&agrave; come E11.5 e la sintesi del DNA aberrante nel vano cella fibra di E14.5. Analisi di espressione genica hanno dimostrato che sulla perdita di Notch2, ci sono stati livelli elevati del ciclo delle cellule regolatori Cdkn1a (p21Cip1), Ccnd2 (CyclinD2) e Trp63 (p63) che regola negativamente segnalazione Wnt, oltre a down-regulation di Cdh1 (E-caderina). Rimozione di Notch2 ha portato anche in una percentuale maggiore di cellule di fibra, come &egrave; stato trovato in Rbpj e Jag1 lenti mutante condizionale. Tuttavia, Notch2 non &egrave; necessaria per la proliferazione di AEL, suggerendo che un recettore diverso regola questo processo. Abbiamo trovato che la Notch2 blocca normalmente lente progenitrici delle cellule morte. In generale, possiamo concludere che Notch2-mediata segnalazione regola la morfogenesi lente, apoptosi, ritiro del ciclo cellulare e differenziamento cellulare fibra secondaria.

Ablazione condizionale del recettore Notch2 la lente oculare.

Notch&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x306F;&#x3001;&#x9069;&#x5207;&#x306A;&#x30EC;&#x30F3;&#x30BA;&#x306E;&#x958B;&#x767A;&#x306E;&#x305F;&#x3081;&#x306B;&#x3057;&#x304B;&#x3057;&#x3001;&#x500B;&#x3005;&#x306E;Notch&#x53D7;&#x5BB9;&#x4F53;&#x306E;&#x7279;&#x5B9A;&#x306E;&#x8981;&#x4EF6;&#x304C;&#x691C;&#x8A0E;&#x3055;&#x308C;&#x3066;&#x3044;&#x306A;&#x3044;&#x304C;&#x4E0D;&#x53EF;&#x6B20;&#x3067;&#x3042;&#x308B;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x30EC;&#x30F3;&#x30BA;&#x306E;&#x91CD;&#x7BE4;&#x306A;&#x773C;&#x7403;&#x3092;&#x793A;&#x3057;&#x305F;Notch2&#x6761;&#x4EF6;&#x4ED8;&#x304D;&#x5909;&#x7570;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x8868;&#x73FE;&#x578B;&#x3001;&#x6E1B;&#x5C11;&#x77B3;&#x5B54;&#x306E;&#x958B;&#x53E3;&#x90E8;&#x306F;&#x3001;&#x7E4A;&#x7DAD;&#x7D30;&#x80DE;&#x5F62;&#x614B;&#x3092;&#x7834;&#x58CA;&#x3057;&#x3001;&#x524D;&#x65B9;&#x306E;&#x4E0A;&#x76AE;&#x3001;&#x7E4A;&#x7DAD;&#x7D30;&#x80DE;&#x306E;&#x767A;&#x80B2;&#x4E0D;&#x5168;&#x306E;&#x6700;&#x7D42;&#x7684;&#x306A;&#x640D;&#x5931;&#x3001;&#x8131;&#x6838;&#x6B20;&#x9665;&#x3001;&#x767D;&#x5185;&#x969C;&#x3092;&#x5831;&#x544A;&#x3057;&#x307E;&#x3059;&#x3002; Notch2&#x5909;&#x7570;&#x4F53;&#x306F;&#x307E;&#x305F;&#x3001;E14.5 E11.5&#x3067;&#x65E9;&#x304F;&#x3082;&#x3001;&#x7E4A;&#x7DAD;&#x7D30;&#x80DE;&#x306E;&#x30B3;&#x30F3;&#x30D1;&#x30FC;&#x30C8;&#x30E1;&#x30F3;&#x30C8;&#x5185;&#x306E;&#x7570;&#x5E38;&#x306A;DNA&#x5408;&#x6210;&#x306E;&#x3088;&#x3046;&#x306A;&#x6C38;&#x7D9A;&#x7684;&#x306A;&#x30EC;&#x30F3;&#x30BA;&#x306E;&#x830E;&#x3092;&#x6301;&#x3063;&#x3066;&#x3044;&#x305F;&#x3002;&#x907A;&#x4F1D;&#x5B50;&#x767A;&#x73FE;&#x89E3;&#x6790;&#x306F;&#x3001;Notch2&#x306E;&#x640D;&#x5931;&#x6642;&#x306B;&#x3001;&#x8CA0;&#x306E;Wnt&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x3092;&#x8ABF;&#x7BC0;&#x3059;&#x308B;&#x7D30;&#x80DE;&#x5468;&#x671F;&#x8ABF;&#x7BC0;&#x56E0;&#x5B50;CDKN1A&#xFF08;p21Cip1&#xFF09;&#x3001;Ccnd2&#xFF08;CyclinD2&#xFF09;&#x3001;&#x304A;&#x3088;&#x3073;Trp63&#xFF08;P63&#xFF09;&#x306E;&#x4E0A;&#x6607;&#x304C;&#x3042;&#x3063;&#x305F;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3001;&#x30D7;&#x30E9;&#x30B9;CDH1&#xFF08;E-&#x30AB;&#x30C9;&#x30D8;&#x30EA;&#x30F3;&#x306E;&#x30C0;&#x30A6;&#x30F3;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x3002;&#xFF09; Rbpj&#x3068;JAG1&#x6761;&#x4EF6;&#x5909;&#x7570;&#x4F53;&#x30EC;&#x30F3;&#x30BA;&#x3067;&#x767A;&#x898B;&#x3055;&#x308C;&#x305F;&#x3068;&#x3057;&#x3066;Notch2&#x306E;&#x9664;&#x53BB;&#x306F;&#x307E;&#x305F;&#x3001;&#x7E4A;&#x7DAD;&#x7D30;&#x80DE;&#x306E;&#x5272;&#x5408;&#x306E;&#x5897;&#x52A0;&#x3092;&#x3082;&#x305F;&#x3089;&#x3057;&#x305F;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;Notch2&#x306F;&#x3001;&#x7570;&#x306A;&#x308B;&#x53D7;&#x5BB9;&#x4F53;&#x304C;&#x3053;&#x306E;&#x30D7;&#x30ED;&#x30BB;&#x30B9;&#x3092;&#x5236;&#x5FA1;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3001;AEL&#x5897;&#x6B96;&#x306B;&#x5FC5;&#x9808;&#x3067;&#x306F;&#x3042;&#x308A;&#x307E;&#x305B;&#x3093;&#x3002;&#x6211;&#x3005;&#x306F;&#x3001;Notch2&#x901A;&#x5E38;&#x306F;&#x30D6;&#x30ED;&#x30C3;&#x30AF;&#x30EC;&#x30F3;&#x30BA;&#x524D;&#x99C6;&#x7D30;&#x80DE;&#x6B7B;&#x3092;&#x767A;&#x898B;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x5168;&#x4F53;&#x3068;&#x3057;&#x3066;&#x3001;&#x6211;&#x3005;&#x306F;Notch2&#x3092;&#x4ECB;&#x3059;&#x308B;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x306F;&#x3001;&#x30EC;&#x30F3;&#x30BA;&#x306E;&#x5F62;&#x614B;&#x5F62;&#x6210;&#x3001;&#x30A2;&#x30DD;&#x30C8;&#x30FC;&#x30B7;&#x30B9;&#x3001;&#x7D30;&#x80DE;&#x5468;&#x671F;&#x306E;&#x64A4;&#x9000;&#x3001;&#x304A;&#x3088;&#x3073;&#x4E8C;&#x6B21;&#x7E4A;&#x7DAD;&#x7D30;&#x80DE;&#x306E;&#x5206;&#x5316;&#x3092;&#x5236;&#x5FA1;&#x3059;&#x308B;&#x3068;&#x7D50;&#x8AD6;&#x4ED8;&#x3051;&#x3066;&#x3044;&#x308B;&#x3002;

&#x63A5;&#x773C;&#x30EC;&#x30F3;&#x30BA;&#x306E;Notch2&#x53D7;&#x5BB9;&#x4F53;&#x306E;&#x6761;&#x4EF6;&#x30A2;&#x30D6;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;

&#xADF8;&#xB7EC;&#xB098; &#xB178;&#xCE58; &#xC2E0;&#xD638; &#xAC1C;&#xBCC4; &#xB178;&#xCE58; &#xC218;&#xC6A9; &#xCCB4;&#xC758; &#xD2B9;&#xC815; &#xC694;&#xAD6C; &#xC0AC;&#xD56D;&#xC744; &#xC870;&#xC0AC; &#xD558;&#xC9C0; &#xC54A;&#xC740; &#xC801;&#xC808; &#xD55C; &#xB80C;&#xC988; &#xAC1C;&#xBC1C;&#xC744; &#xC704;&#xD574; &#xD544;&#xC218;&#xC801; &#xC774;&#xB2E4;. &#xC5EC;&#xAE30; &#xC6B0;&#xB9AC;&#xB294; &#xC2EC;&#xAC01;&#xD55C; microphthalmia &#xC804;&#xC2DC;, &#xB3D9; &#xACF5; &#xAD6C;&#xBA4D; &#xAC10;&#xC18C;, &#xC12C;&#xC720; &#xC138;&#xD3EC; &#xD615;&#xD0DC;&#xD559;, &#xC55E;&#xCABD;&#xC5D0; &#xC0C1;&#xD53C;, &#xC12C;&#xC720; &#xC140; dysgenesis, denucleation &#xACB0;&#xD568; &#xBC31; &#xB0B4;&#xC7A5;&#xC758; &#xACB0;&#xACFC;&#xC801;&#xC778; &#xC190;&#xC2E4;&#xC5D0; &#xCC28;&#xC9C8;&#xC774; Notch2 &#xC870;&#xAC74;&#xC5D0; &#xB530;&#xB77C; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xC0DD;&#xC950;&#xC758; &#xB80C;&#xC988; &#xACE0;&#xAE30; &#xBCF4;&#xACE0; &#xD569;&#xB2C8;&#xB2E4;. Notch2 &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; E14.5&#xC5D0; &#xC758;&#xD574; &#xC12C;&#xC720; &#xC140; &#xAD6C;&#xD68D;&#xC5D0;&#xC11C; &#xC601;&#xAD6C; &#xB80C;&#xC988; &#xC904;&#xAE30; &#xC77C;&#xCC0D; E11.5, &#xADF8;&#xB9AC;&#xACE0; &#xD0C8; &#xC120; DNA &#xD569;&#xC131; &#xD588;&#xB2E4;. &#xC9C4; &#xC2DD; &#xBD84;&#xC11D; &#xD588;&#xB2E4; notch2&#xC758; &#xC190;&#xC2E4;&#xC5D0; &#xB530;&#xB77C; &#xB192;&#xC740; &#xC218;&#xC900;&#xC758; &#xC138;&#xD3EC; &#xC8FC;&#xAE30; &#xB808; &#xADE4; &#xB808;&#xC774; &#xD130; Cdkn1a (p21Cip1), ccnd2&#xAC00; &#xC788;&#xB2E4;&#xACE0; (CyclinD2), &#xBC0F; trp63&#xB294; &#xBD80;&#xC815;&#xC801;&#xC778; Wnt &#xC2E0;&#xD638; &#xD50C;&#xB7EC;&#xC2A4; cdh1&#xC758; &#xB2E4;&#xC6B4; &#xB808; &#xADE4; &#xB808;&#xC774; &#xC158; (p63) &#xADDC;&#xC81C; (&#xC804;&#xC790; Cadherin). Notch2&#xC758; &#xC81C;&#xAC70; &#xB610;&#xD55C; &#xACB0;&#xACFC; &#xC12C;&#xC720; &#xC138;&#xD3EC;&#xC758; &#xC99D;&#xAC00; &#xBE44;&#xC728; Rbpj&#xACFC; Jag1 &#xC870;&#xAC74;&#xBD80; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xB80C;&#xC988;&#xC5D0;&#xC11C; &#xBC1C;&#xACAC; &#xB418;&#xC5C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, Notch2 &#xD544;&#xC694; &#xD558;&#xC9C0; &#xC54A;&#xC2B5;&#xB2C8;&#xB2E4; AEL &#xD655;&#xC0B0;&#xC5D0; &#xB300; &#xD55C; &#xB2E4;&#xB978; &#xC218;&#xC6A9; &#xCCB4;&#xAC00;&#xC774; &#xACFC;&#xC815;&#xC744; &#xC870;&#xC808; &#xD558;&#xC790;. Notch2 &#xC77C;&#xBC18;&#xC801;&#xC73C;&#xB85C; &#xB80C;&#xC988; &#xC870;&#xC0C1; &#xC138;&#xD3EC; &#xC8FD;&#xC74C; &#xCC28;&#xB2E8;&#xB97C; &#xCC3E;&#xC558;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC804;&#xBC18;&#xC801;&#xC73C;&#xB85C;, &#xC6B0;&#xB9AC;&#xB294; &#xB80C;&#xC988; morphogenesis, apoptosis, &#xC138;&#xD3EC; &#xC8FC;&#xAE30; &#xCCA0;&#xC218; &#xBC0F; &#xBCF4;&#xC870; &#xC12C;&#xC720; &#xC138;&#xD3EC; &#xBD84;&#xD654; &#xC870;&#xC808; &#xC2E0;&#xD638; Notch2 &#xC911;&#xC7AC; &#xACB0;&#xB860;.

&#xB208; &#xB80C;&#xC988;&#xC5D0; Notch2 &#xC218;&#xC6A9; &#xCCB4;&#xC758; &#xC870;&#xAC74;&#xBD80; &#xC808;&#xC81C;.

Se&#xF1;alizaci&#xF3;n Notch es esencial para el desarrollo lente adecuada, sin embargo los requisitos espec&#xED;ficos de receptores Notch individuales no han sido investigados. Aqu&#xED; mostramos los fenotipos de la lente de Notch2 los ratones mutantes condicionalmente, que presentaban severas microftalmia, la reducci&#xF3;n de las aberturas pupilares, interrumpido morfolog&#xED;a de las c&#xE9;lulas de fibra, la eventual p&#xE9;rdida del epitelio anterior de disgenesia, c&#xE9;lula de la fibra, defectos denucleation y cataratas. Notch2 mutantes tambi&#xE9;n ten&#xED;an tallos persistentes lentes tan pronto como E11.5 y la s&#xED;ntesis de ADN aberrante en el compartimento de c&#xE9;lulas de fibra por E14.5. Los an&#xE1;lisis de expresi&#xF3;n g&#xE9;nica mostraron que, tras la p&#xE9;rdida de Notch2, hab&#xED;a niveles elevados de la del ciclo celular reguladores CDKN1A (p21Cip1), Ccnd2 (CyclinD2), y Trp63 (p63), que regula negativamente la se&#xF1;alizaci&#xF3;n de Wnt, adem&#xE1;s de la baja regulaci&#xF3;n de Cdh1 (E-cadherina ). La eliminaci&#xF3;n de Notch2 tambi&#xE9;n dio lugar a una mayor proporci&#xF3;n de c&#xE9;lulas de fibra, como se constat&#xF3; en Rbpj y JAG1 lentes de mutantes condicionales. Sin embargo, Notch2 no es necesario para la proliferaci&#xF3;n AEL, lo que sugiere que un receptor diferente regula este proceso. Hemos encontrado que Notch2 normalmente lente bloques progenitora la muerte celular. En general, llegamos a la conclusi&#xF3;n de que Notch2 regula la se&#xF1;alizaci&#xF3;n mediada por la morfog&#xE9;nesis del objetivo, la apoptosis, la retirada del ciclo celular y la diferenciaci&#xF3;n de c&#xE9;lulas de fibra secundaria.

La ablaci&#xF3;n condicional del receptor Notch2 en el lente ocular

CD4⁺CD25⁺Foxp3⁺ T lymphocytes, known as regulatory T cells or T(regs), have been proposed to be a lineage of professional immune suppressive cells that exclusively counteract the effects of the immunoprotective "helper" and "cytotoxic" lineages of T lymphocytes. Here we discuss new concepts on the mechanisms and functions of T(regs). There are several key points we emphasize: 1. Tregs exert suppressive effects both directly on effector T cells and indirectly through antigen-presenting cells; 2. Regulation can occur through a novel mechanism of cytokine consumption to regulate as opposed to the usual mechanism of cytokine/chemokine production; 3. In cases where CD4⁺ effector T cells are directly inhibited by T(regs), it is chiefly through a mechanism of lymphokine withdrawal apoptosis leading to polyclonal deletion; and 4. Contrary to the current view, we discuss new evidence that T(regs), similar to other T-cells lineages, can promote protective immune responses in certain infectious contexts (Chen et al., 2011; Pandiyan et al., 2011). Although these points are at variance to varying degrees with the standard model of T(reg) behavior, we will recount developing findings that support these new concepts.

The molecular mechanisms of regulatory T cell immunosuppression.

Comment on "Cutting edge: regulatory T cells do not mediate suppression via programmed cell death pathways".

IL-15 is an important IL-2-related cytokine whose role in Th17 cell biology has not been fully elucidated. In this study, we show that exogenous IL-15 decreased IL-17A production in Th17 cultures. Neutralization of IL-15 using an Ab led to increases in IL-17A production in Th17 cultures. Both Il15(-/-) and Il15r(-/-) T cell cultures displayed higher frequency of IL-17A producers and higher amounts of IL-17A in the supernatants compared with those of wild-type (WT) cells in vitro. IL-15 down-modulated IL-17A production independently of retinoic acid-related orphan receptor-γt, Foxp3, and IFN-γ expression. Both Th17 cells and APCs produced IL-15, which induced binding of STAT5, an apparent repressor to the Il17 locus in CD4 T cells. Also, in a model of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE), Il15(-/-) mice displayed exacerbated inflammation-correlating with increased IL-17A production by their CD4(+) T cells-compared with WT controls. Exogenous IL-15 administration and IL-17A neutralization reduced the severity of EAE in Il15(-/-) mice. Taken together, these data indicate that IL-15 has a negative regulatory role in fine-tuning of IL-17A production and Th17-mediated inflammation.

The role of IL-15 in activating STAT5 and fine-tuning IL-17A production in CD4 T lymphocytes.

Utilizing mouse models provides excellent immunological and experimental tools to study oral immune responses. However for functional assays, isolating T lymphocytes from the oral tissues has proved to be challenging due to the absence of reliable methods that yield viable cells with consistency. To study adaptive immune cell interactions in the oral mucosal tissues, it is necessary to isolate T cells with a good viability and study them at the single cell level.

Pushpa Pandiyan

Department of Biological Sciences,
School of Dental Medicine,
Department of Biological Sciences, School of Dental Medicine

Case Western Reserve University

Th17 Inflammation Model of Oropharyngeal Candidiasis in Immunodeficient Mice

Pushpa Pandiyan

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Biological Sciences,School of Dental Medicine,Department of Biological Sciences, School of Dental Medicine

Case Western Reserve University

Th17 Inflammation Model of Oropharyngeal Candidiasis in Immunodeficient Mice

Department of Biological Sciences,
School of Dental Medicine,
Department of Biological Sciences, School of Dental Medicine