analysis-microglia-monocyte-derived-macrophages-from-central-nervous

Analysis of Microglia and Monocyte-derived Macrophages from the Central Nervous System by Flow Cytometry

Numerous studies have demonstrated the role of immune cells, in particular macrophages, in central nervous system (CNS) pathologies. There are two main ...

Inserm U 1227, CNRS UMR 7225

UPMC, University of Paris

Institut du Cerveau et de la Moelle épinière, ICM

We described previously a CTL clone able to lyse the autologous carcinoma cell line IGR-Heu after specific recognition of an HLA-A2/mutated alpha-actinin-4 peptide complex. Here, we used IGR-Heu, cultured either as standard two-dimensional monolayers or as three-dimensional spheroids, to further analyze the influence of target architecture on CTL reactivity. Interestingly, we found that changes in the tumor structure from two- to three-dimensional induced a dramatic decrease in its capacity to activate autologous CTL, as measured by IFN-gamma and tumor necrosis factor-alpha secretion. These functional alterations were attributable neither to MHC class I expression nor to tumor antigen (Ag) down-regulation, because IGR-Heu, cultured as two- or three-dimensional, expressed similar levels of HLA-A2 and alpha-actinin-4. More importantly, incubation of three-dimensional cells with synthetic epitope completely restored cytokine release by CTL. This defective Ag presentation correlated with a decrease in heat shock protein (hsp)70 expression by three-dimensional tumors compared with two-dimensional cells. Furthermore, transfection of the tumor cells with hsp70 cDNA completely restored the Ag-presenting potential of spheroids and, therefore, cytokine production by T cells. These data strongly suggest that hsp70 down-regulation in three-dimensional cells may result in tumor resistance to the immune response.

A three-dimensional tumor cell defect in activating autologous CTLs is associated with inefficient antigen presentation correlated with heat shock protein-70 down-regulation.

Animal models of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) are inflammatory demyelinating diseases which comprise a heterogeneous group of disorders that affect the peripheral and central nervous systems. EAE presents close similarities with multiple sclerosis (MS), a chronic inflammatory disease affecting central nervous system (CNS) white matter. Many studies have shown EAE to be a particularly useful animal model for the understanding of both the mechanisms of immune-mediated CNS pathology and the progressive clinical course of multiple sclerosis. Previous data has underlined the importance of CD4+ T cell involvement in mediating the autoimmune processes associated with the destruction of myelin and the role of the T helper 1 (Th1) pattern of cytokine secretion. However, EAE studies have also demonstrated that other cells involved in innate and/or adaptive immune responses may also play a critical role in the early and progressive events of the immune reaction leading to inflammation and CNS damage. In this review, we present such new data and discuss their potent implication for future new therapeutical approaches.

New insights into cell responses involved in experimental autoimmune encephalomyelitis and multiple sclerosis.

We sequentially analyzed the serum IgG response against normal mouse brain during experimental autoimmune encephalomyelitis in SJL/J mice injected with CFA, Bordetella pertussis toxin (BPT) and proteolipid protein 139-151 peptide, compared with mice that received CFA and BPT or were uninjected. Dynamic changes were observed from day 0 to day 28 in the 3 groups. Six highly discriminant antigenic bands (kappa=0.974) were identified. Three non-myelin proteins were characterized (mitochondrial aconitase hydratase 2, phosphoglycerate mutase 1, brain specific pyruvate deshydrogenase). The IgG response against two of them was less frequent in EAE whereas it was associated with multiple sclerosis in our previous work.

Diversified serum IgG response involving non-myelin CNS proteins during experimental autoimmune encephalomyelitis.

We reduced EAE severity by using two anti-allergic drugs. A control group of mice received i.p. injections of PBS as vehicle while a further two groups were treated either with pyrilamine, a histamine receptor 1 antagonist or with CV6209, a platelet activating factor receptor antagonist. Our results showed that the blockade of the responses to both histamine and PAF leads together to a decline in clinical signs of EAE and significant changes in the serum IgG recognition of some healthy brain antigenic targets. We characterized two discriminant antigens: internexin neuronal intermediate filament protein, and malate dehydrogenase 1, which were able to clearly distinguish untreated mice from treated mice. Their role as potent targets in pathogenic and/or neuroprotective processes is discussed.

Changes in self-reactive IgG antibody repertoire after treatment of experimental autoimmune encephalomyelitis with anti-allergic drugs.

&#x611F;&#x67D3;&#x548C;&#x81EA;&#x8EAB;&#x514D;&#x75AB;&#x5C0F;&#x9F20;&#x7F3A;&#x4E4F;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20; 27 (IL-27) &#x53D7;&#x4F53;&#x7684; &alpha;-&#x4E9A;&#x5355;&#x4F4D;&#x671F;&#x95F4;&#x53D1;&#x751F;&#x8FC7;&#x5EA6;&#x7684;&#x708E;&#x75C7;&#x53CD;&#x5E94;&#x3002;&#x4F9D;&#x636E;&#x6B64;&#x589E;&#x52A0;&#x7684;&#x708E;&#x75C7;&#x7684;&#x5206;&#x5B50;&#x673A;&#x5236;&#x90FD;&#x6CA1;&#x6709;&#x5B8C;&#x5168;&#x641E;&#x6E05;&#x695A;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x62A5;&#x544A;&#x7684; IL-27 &#x589E;&#x9AD8;&#x6548;&#x5E94; T &#x7EC6;&#x80DE;&#x4EA7;&#x751F;&#x5E72;&#x6270;&#x7D20;&#x548C;&#x8868;&#x793A;&#x8F6C;&#x5F55;&#x56E0;&#x5B50; T &#x6253;&#x8D4C;&#xFF0C;&#x4F46;&#x5E76;&#x6CA1;&#x6709;&#x8868;&#x793A;&#x8F6C;&#x5F55;&#x56E0;&#x5B50; Foxp3 &#x5728; IL-10&#x3002;&#x8FD9;&#x4E9B;&#x5E72;&#x6270;&#x7D20; &gamma; + T-&#x4E0B;&#x6CE8; + Foxp3 &#x7EC6;&#x80DE;&#x7C7B;&#x4F3C;&#x6548;&#x5E94; T &#x7EC6;&#x80DE;&#x5728;&#x708E;&#x75C7;&#x671F;&#x95F4;&#x5DF2;&#x786E;&#x5B9A;&#x4F5C;&#x4E3A;&#x4E3B;&#x673A;&#x4FDD;&#x62A4;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-10 &#x7684;&#x4E3B;&#x8981;&#x6765;&#x6E90;&#x3002;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-10 &#x8BF1;&#x5BFC;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20; 27 &#x751F;&#x4EA7;&#x662F;&#x5173;&#x8054;&#x8F83;&#x5C11;&#x5206;&#x6CCC;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-17 &#x7684;&#x548C;&#x5916;&#x6E90;&#x6027; IL-27 &#x51CF;&#x5C11;&#x673A;&#x5236;&#x4F9D;&#x8D56;&#x4E8E; IL-10 adoptively &#x4F20;&#x8F93;&#x5B9E;&#x9A8C;&#x6027;&#x81EA;&#x8EAB;&#x514D;&#x75AB;&#x6027;&#x8111;&#x810A;&#x9AD3;&#x708E;&#x7684;&#x4E25;&#x91CD;&#x7A0B;&#x5EA6;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x6570;&#x636E;&#x663E;&#x793A;&#x7531;&#x6548;&#x5E94; T &#x7EC6;&#x80DE;&#x7684;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-10 &#x8BF1;&#x5BFC;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20; 27 &#x751F;&#x4EA7;&#x6709;&#x52A9;&#x4E8E;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20; 27 &#x7684;&#x514D;&#x75AB;&#x8C03;&#x8282;&#x4F5C;&#x7528;&#x3002;

&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20; 10 &#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20; 27 &#x523A;&#x6FC0; T &#x7EC6;&#x80DE;&#x5206;&#x6CCC;&#x7684;&#x4E2D;&#x67A2;&#x795E;&#x7ECF;&#x7CFB;&#x7EDF;&#x7684;&#x81EA;&#x8EAB;&#x514D;&#x75AB;&#x6027;&#x708E;&#x75C7;&#x7684;&#x6291;&#x5236;&#x3002;

Excessive inflammation occurs during infection and autoimmunity in mice lacking the alpha-subunit of the interleukin 27 (IL-27) receptor. The molecular mechanisms underlying this increased inflammation are incompletely understood. Here we report that IL-27 upregulated IL-10 in effector T cells that produced interferon-gamma and expressed the transcription factor T-bet but did not express the transcription factor Foxp3. These IFN-gamma+T-bet+Foxp3- cells resembled effector T cells that have been identified as the main source of host-protective IL-10 during inflammation. IL-27-induced production of IL-10 was associated with less secretion of IL-17, and exogenous IL-27 reduced the severity of adoptively transferred experimental autoimmune encephalomyelitis by a mechanism dependent on IL-10. Our data show that IL-27-induced production of IL-10 by effector T cells contributes to the immunomodulatory function of IL-27.

Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells.

Inflammation excessive se produit pendant l&#39;infection et l&#39;auto-immunit&eacute; chez les souris manquant de la sous-unit&eacute; alpha du r&eacute;cepteur de l&#39;interleukine 27 (IL-27). Les m&eacute;canismes mol&eacute;culaires qui sous-tendent cette inflammation accrue sont encore partiellement comprises. Nous rapportons ici que IL-27 surexprim&eacute;s IL-10 dans les cellules effectrices T qui produit de l&#39;interf&eacute;ron-gamma et exprim&eacute; le facteur de transcription T-bet mais n&#39;exprimait pas le facteur de transcription Foxp3. Ces IFN-gamma + T-pari + Foxp3-cellules ressemblent aux cellules effectrices T qui ont &eacute;t&eacute; identifi&eacute;s comme la source principale de protection h&ocirc;te IL-10, lors d&#39;une inflammation. IL 27-induite par la production d&#39;IL-10 a &eacute;t&eacute; associ&eacute;e &agrave; moins de s&eacute;cr&eacute;tion d&#39;IL-17 et exog&egrave;ne d&#39;IL-27 r&eacute;duit la s&eacute;v&eacute;rit&eacute; de l&#39;enc&eacute;phalomy&eacute;lite allergique exp&eacute;rimentale Moutschen transf&eacute;r&eacute; par un m&eacute;canisme d&eacute;pendant de l&#39;IL-10. Nos r&eacute;sultats montrent que la production d&#39;IL-10 par les cellules effectrices T induite par l&#39;IL-27 contribue &agrave; la fonction immunomodulatrices d&#39;IL-27.

Suppression de l&#39;inflammation auto-immune du syst&egrave;me nerveux central par interleukine 10 s&eacute;cr&eacute;t&eacute;e par des cellules de T 27 stimul&eacute;e par interleukine.

&Uuml;berm&auml;&szlig;ige Entz&uuml;ndung tritt w&auml;hrend der Infektion und Autoimmunit&auml;t in M&auml;usen fehlt der Alpha-Untereinheit des Interleukin-Rezeptors f&uuml;r 27 (IL-27). Die molekularen Mechanismen dieser erh&ouml;hten Entz&uuml;ndungen sind unvollst&auml;ndig verstanden. Hier berichten wir, dass IL-27 herraufreguliert IL-10 in T-Effektorzellen, die produzierte Interferon-Gamma und Transkriptionsfaktors T-Bet ausgedr&uuml;ckt aber nicht ausdr&uuml;cken, Transkriptionsfaktors Foxp3. Diese IFN-Gamma + T-Wette + Foxp3-Zellen glich T-Effektorzellen, die als die Hauptquelle der Host-Schutz-und IL-10 bei Entz&uuml;ndung ermittelt wurden. IL-27-induzierte Produktion von IL-10 wurde mit weniger Sekretion von IL-17 und exogene IL-27 reduziert den Schweregrad der adoptively &uuml;bertragenen experimentellen autoimmunen Enzephalomyelitis durch einen Mechanismus abh&auml;ngig von IL-10. Unsere Daten zeigen, dass IL-27-induzierte Produktion von IL-10 durch T-Effektorzellen der immunmodulatorische Funktion der IL-27 tr&auml;gt.

Unterdr&uuml;ckung der autoimmune Entz&uuml;ndung des zentralen Nervensystems durch Interleukin 10 abgesondert durch Interleukin 27-stimuliert die T-Zellen.

Eccessiva infiammazione si verifica durante l&#39;infezione e autoimmunit&agrave; in topi cui manca la subunit&agrave; alfa del recettore interleuchina 27 (IL-27). I meccanismi molecolari alla base di questa infiammazione aumentata in modo incompleto sono capiti. Qui riportiamo quello sovraregolati IL 27 IL-10 in cellule effettrici T che ha prodotto l&#39;interferone-gamma ed espresso il fattore di trascrizione T-bet, ma non si &egrave; espresso il fattore di trascrizione Foxp3. Questi IFN-gamma + T-cellule scommessa + Foxp3 somigliava a cellule effettrici T che sono state identificate come la fonte principale di host-protettivo IL-10 durante l&#39;infiammazione. IL 27-indotta la produzione di IL-10 &egrave; stata associata con minore secrezione di IL-17, e IL esogeno-27 ridotta gravit&agrave; dell&#39;encefalomielite autoimmune sperimentale adoptively trasferita da un meccanismo dipendente da IL-10. I nostri dati mostrano che IL 27-indotta la produzione di IL-10 da parte delle cellule T effettrici contribuisce alla funzione immunomodulatori di IL-27.

Soppressione di infiammazione autoimmune del sistema nervoso centrale di interleuchina 10 secernuti dalla interleuchina 27-stimolato le cellule T.

&#x904E;&#x5270;&#x306A;&#x708E;&#x75C7;&#x306B;&#x611F;&#x67D3;&#x75C7;&#x3084;&#x81EA;&#x5DF1;&#x514D;&#x75AB;&#x306E;&#x30A4;&#x30F3;&#x30BF;&#x30FC;&#x30ED;&#x30A4;&#x30AD;&#x30F3; 27 (IL-27) &#x53D7;&#x5BB9;&#x4F53; &alpha; &#x30B5;&#x30D6;&#x30E6;&#x30CB;&#x30C3;&#x30C8;&#x6B20;&#x640D;&#x30DE;&#x30A6;&#x30B9;&#x3067;&#x767A;&#x751F;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x306E;&#x5897;&#x52A0;&#x708E;&#x75C7;&#x306E;&#x5206;&#x5B50;&#x306E;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x306F;&#x4E0D;&#x5B8C;&#x5168;&#x306B;&#x7406;&#x89E3;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;IL 27 &#x767A;&#x73FE;&#x4EA2;&#x9032; IL-10 &#x30A4;&#x30F3;&#x30BF;&#x30FC;&#x30D5;&#x30A7;&#x30ED;&#x30F3;-&gamma; &#x3092;&#x751F;&#x6210;&#x3057;&#x3001;&#x8EE2;&#x5199;&#x56E0;&#x5B50; t-bet &#x306E;&#x8868;&#x73FE;&#x304C;&#x3001;&#x8EE2;&#x5199;&#x56E0;&#x5B50; Foxp3 &#x3092;&#x8868;&#x73FE;&#x3057;&#x306A;&#x304B;&#x3063;&#x305F;&#x30A8;&#x30D5;&#x30A7;&#x30AF;&#x30BF;&#x30FC; T &#x7D30;&#x80DE;&#x3067;&#x5831;&#x544A;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E; IFN-&gamma; + T-&#x30D9;&#x30C3;&#x30C8; + Foxp3 &#x7D30;&#x80DE;&#x30DB;&#x30B9;&#x30C8;&#x4FDD;&#x8B77; IL-10 &#x306E;&#x4E3B;&#x306A;&#x30BD;&#x30FC;&#x30B9;&#x3068;&#x3057;&#x3066;&#x306F;&#x708E;&#x75C7;&#x306E;&#x9593;&#x306B;&#x8B58;&#x5225;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x30A8;&#x30D5;&#x30A7;&#x30AF;&#x30BF;&#x30FC; T &#x7D30;&#x80DE;&#x306B;&#x4F3C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;IL &#x8A98;&#x8D77; 27 &#x751F;&#x7523; IL-10 &#x306E; IL-17 &#x306E;&#x5206;&#x6CCC;&#x304C;&#x6E1B;&#x5C11;&#x3059;&#x308B;&#x3068;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x3044;&#x308B;&#x3068;&#x5916;&#x56E0;&#x6027; IL 27 IL-10 &#x306B;&#x4F9D;&#x5B58;&#x306E;&#x6A5F;&#x69CB;&#x306B;&#x5BFE;&#x3057;&#x3066;&#x8EE2;&#x9001;&#x5B9F;&#x9A13;&#x7684;&#x81EA;&#x5DF1;&#x514D;&#x75AB;&#x6027;&#x8133;&#x810A;&#x9AC4;&#x708E;&#x306E;&#x91CD;&#x75C7;&#x5EA6;&#x3092;&#x524A;&#x6E1B;&#x3057;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005; &#x306E;&#x30C7;&#x30FC;&#x30BF;&#x306F; IL &#x8A98;&#x8D77; 27 &#x751F;&#x7523; IL-10 &#x30A8;&#x30D5;&#x30A7;&#x30AF;&#x30BF;&#x30FC; T &#x7D30;&#x80DE;&#x306E; IL 27 &#x306E;&#x514D;&#x75AB;&#x8ABF;&#x7BC0;&#x6A5F;&#x80FD;&#x306B;&#x5BC4;&#x4E0E;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x898B;&#x308B;&#x3002;

&#x4E2D;&#x67A2;&#x795E;&#x7D4C;&#x7CFB;&#x306B;&#x3088;&#x308B;&#x30A4;&#x30F3;&#x30BF;&#x30FC;&#x30ED;&#x30A4;&#x30AD;&#x30F3; &#x30A4;&#x30F3;&#x30BF;&#x30FC;&#x30ED;&#x30A4;&#x30AD;&#x30F3; 27 &#x523A;&#x6FC0; T &#x7D30;&#x80DE;&#x306B;&#x3088;&#x3063;&#x3066;&#x5206;&#x6CCC;&#x3055;&#x308C;&#x308B; 10 &#x306E;&#x81EA;&#x5DF1;&#x514D;&#x75AB;&#x6027;&#x708E;&#x75C7;&#x306E;&#x6291;&#x5236;&#x3002;

&#xACFC;&#xB3C4; &#xD55C; &#xC5FC;&#xC99D;&#xC744; &#xB9C8;&#xC6B0;&#xC2A4; &#xC778;&#xD130; &#xB8E8; &#xD0A8; 27 (IL-27) &#xC218;&#xC6A9; &#xCCB4;&#xC758; &#xC54C;&#xD30C; &#xC18C; &#xB2E8;&#xC704; &#xBD80;&#xC871;&#xC5D0;&#xC11C; &#xC790;&#xAC00; &#xBA74;&#xC5ED; &#xBC0F; &#xAC10;&#xC5FC; &#xBC1C;&#xC0DD; &#xD569;&#xB2C8;&#xB2E4;. &#xAE30;&#xBCF8;&#xC774; &#xB41C; &#xC5FC;&#xC99D; &#xC99D;&#xAC00; &#xD558;&#xB294; &#xBD84;&#xC790; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC740; &#xBD88;&#xC644;&#xC804; &#xD558; &#xAC8C; &#xC774;&#xD574;. &#xC5EC;&#xAE30; &#xC6B0;&#xB9AC; &#xBCF4;&#xACE0;&#xB294; IL-27 upregulated IL-10 &#xC774;&#xD399;&#xD130; T &#xC138;&#xD3EC;&#xB294; &#xC778;&#xD130;&#xD398;&#xB860;-&#xAC10;&#xB9C8;&#xB97C; &#xC0DD;&#xC0B0; &#xD558; &#xACE0; &#xC804;&#xC0AC; &#xC778;&#xC790; T &#xB0B4;&#xAE30; &#xD45C;&#xD604; &#xD558;&#xC9C0;&#xB9CC; &#xB179;&#xC74C; &#xBC29;&#xC1A1; &#xC694;&#xC778; Foxp3 &#xD45C;&#xD604; &#xD558;&#xC9C0; &#xC54A;&#xC558;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; IFN-&#xAC10;&#xB9C8; + T-&#xB0B4;&#xAE30; + Foxp3 &#xC140; &#xB2EE;&#xC740; &#xC5FC;&#xC99D;&#xC744; &#xD558;&#xB294; &#xB3D9;&#xC548; &#xD638;&#xC2A4;&#xD2B8; &#xBCF4;&#xD638; IL-10&#xC758; &#xC8FC;&#xC694; &#xC18C;&#xC2A4;&#xB85C; &#xC2DD;&#xBCC4; &#xB41C; &#xC774;&#xD399;&#xD130; T &#xC138;&#xD3EC;. IL-10&#xC758; &#xC0DD;&#xC0B0; &#xC77C;&#xB9AC;&#xB178;&#xC774; 27 &#xC720;&#xB3C4; IL-17, &#xC801;&#xAC8C; &#xBD84; &#xBE44;&#xC640; &#xAD00;&#xB828; &#xB418;&#xC5C8;&#xACE0; exogenous IL 27 IL-10&#xC5D0; &#xC758;&#xC874; &#xD558;&#xB294; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC5D0; &#xC758;&#xD574; &#xBA74;&#xC5ED; encephalomyelitis adoptively &#xC804;&#xC1A1; &#xB41C; &#xC2E4;&#xD5D8;&#xC758; &#xC2EC;&#xAC01;&#xB3C4; &#xAC10;&#xC18C;. &#xC6B0;&#xB9AC;&#xC758; &#xB370;&#xC774;&#xD130;&#xB294; effector T &#xC138;&#xD3EC;&#xC5D0; &#xC758;&#xD574; IL-10&#xC758; IL 27 &#xC720;&#xB3C4; &#xC0DD;&#xC0B0; &#xC77C;&#xB9AC;&#xB178;&#xC774;-27&#xC758; immunomodulatory &#xD568;&#xC218;&#xC5D0; &#xAE30;&#xC5EC;&#xC744; &#xBCF4;&#xC5EC;&#xC900;&#xB2E4;.

&#xC778;&#xD130; &#xB8E8; &#xD0A8; 10 &#xC778;&#xD130; &#xB8E8; &#xD0A8; 27 &#xC790;&#xADF9; T &#xC138;&#xD3EC;&#xC5D0; &#xC758;&#xD574; &#xBD84; &#xBE44;, &#xC911;&#xCD94; &#xC2E0;&#xACBD; &#xC2DC;&#xC2A4;&#xD15C;&#xC758; &#xC790;&#xAE30; &#xBA74;&#xC5ED; &#xC5FC;&#xC99D;&#xC758; &#xC5B5;&#xC81C;.

Inflamaci&oacute;n excesiva se produce durante la infecci&oacute;n y autoinmunidad en ratones que carecen de la subunidad alfa del receptor de la interleucina 27 (IL-27). Incompleto se entienden los mecanismos moleculares subyacentes a esta mayor inflamaci&oacute;n. Aqu&iacute; divulgamos IL-27 alza IL-10 en c&eacute;lulas efectoras T que produjo interfer&oacute;n-gamma y expresa el factor de transcripci&oacute;n T-apuesta pero no expres&oacute; el factor de transcripci&oacute;n Foxp3. Estos IFN-gamma + T-bet + Foxp3-c&eacute;lulas se asemej&oacute; a c&eacute;lulas efectoras T que se han identificado como la principal fuente de protecci&oacute;n host IL-10 durante la inflamaci&oacute;n. IL-27-inducida por la producci&oacute;n de IL-10 se asoci&oacute; con menos secreci&oacute;n de IL-17, y ex&oacute;genos IL-27 reduce la severidad de la encefalomielitis autoinmune experimental eventualmente transferida por un mecanismo dependiente de IL-10. Nuestros datos muestran que la IL-27-inducida por la producci&oacute;n de IL-10 por c&eacute;lulas efectoras T contribuya a la funci&oacute;n inmunomoduladora de IL-27.

Supresi&oacute;n de la inflamaci&oacute;n autoinmune del sistema nervioso central por Interleucina 10 secretada por c&eacute;lulas T 27-estimulado de interleucina.

IL-17-producing CD8(+) T cells (Tc17) appear to play a role in a range of conditions, such as autoimmunity and cancer. Thus far, Tc17 cells have been only marginally studied, resulting in a paucity of data on their biology and function. We demonstrate that Tc17 and Th17 cells share similar developmental characteristics, including the previously unknown promoting effect of IL-21 on Tc17 cell differentiation and IL-23-dependent expression of IL-22. Both STAT1 and STAT4 are required for optimal development of Tc17 cells and maximal secretion of cytokines. Tc17 cells are cytotoxic, and they can be either pathogenic or nonpathogenic upon adoptive transfer in the model of autoimmune diabetes. Tc17 cells treated with TGF-beta1 plus IL-6 are not diabetogenic, whereas IL-23-treated cells potently induce the disease. IL-17A and IL-17F are necessary but not sufficient for diabetes induction by Tc17 cells. Tc17 cells treated with TGF-beta1 plus IL-6 or IL-23 likely differ in pathogenicity due to their disparate capacity to attract other immune cells and initiate inflammation.

IL-23 drives pathogenic IL-17-producing CD8+ T cells.

IL-27 counters the effect of TGF-beta+IL-6 on naive CD4(+) T cells, resulting in near complete inhibition of de novo Th17 development. In contrast, little is known about the effect of IL-27 on already differentiated Th17 cells. A better understanding of how IL-27 regulates these cells is needed to evaluate the therapeutic potential of IL-27 in Th17 cells-associated diseases. In this study, we show that IL-27 had surprisingly little effect on committed Th17 cells, despite its expression of a functional IL-27R. Contrary to de novo differentiation of Th17 cells, IL-27 did not suppress expression of retinoid-related orphan receptor (ROR)gammat or RORalpha in committed Th17 cells. Consistent with this finding, the frequency of committed Th17 cells and their cytokine secretion remained unaffected by IL-27. Both memory Th17 cells (CD4(+)CD25(-)CD62L(low)) that developed in vivo and encephalitogenic Th17 cells infiltrating the CNS of mice developing experimental autoimmune encephalomyelitis produced similar amounts of IL-17A when reactivated with IL-23 in the absence and presence of exogenous IL-27. Finally, IL-27 failed to suppress encephalitogenicity of Th17 cells in an adoptive transfer of experimental autoimmune encephalomyelitis. Analysis ex vivo of transferred Th17 cells in the spleen and CNS of recipient mice showed that cells retained similar phenotype irrespective of whether cells were treated or not with IL-27. Our data demonstrate that in contrast to inhibition of de novo differentiation of Th17 cells, IL-27 has little or no effect on committed Th17 cells. These findings indicate that therapeutic applications of IL-27 might have a limited efficacy in inflammatory conditions where aggressive Th17 responses have already developed.

Differential effect of IL-27 on developing versus committed Th17 cells.

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune demyelinating diseases of the central nervous system (CNS). Interferon-gamma-producing Th1 and interleukin-17-producing Th17 CD4(+) T helper (Th) cells mediate disease pathogenesis in EAE and likely in MS as well. However, the relative contribution of each Th subset to autoimmune processes in the CNS remains unclear. Emerging data suggest that both Th1 and Th17 cells contribute to CNS autoimmunity, albeit through different mechanisms. A better understanding of the roles that Th1 and Th17 cells play in autoimmune inflammation will be helpful in developing new therapeutic approaches. In this review, we discuss recent findings on the roles of Th1 and Th17 cells in the pathogenesis of EAE.

Current views on the roles of Th1 and Th17 cells in experimental autoimmune encephalomyelitis.

17 Interleuchina (IL-17)-produce le cellule T helper (cellule T (H) 17) richiedono una esposizione a IL-23 per diventare encephalitogenic, ma non &egrave; noto il meccanismo mediante il quale IL 23 promuove la loro patogenicit&agrave;. Qui abbiamo trovato che IL 23 indotta da produzione della citochina del granulocyte colony-stimulating factor (GM-CSF) in cellule T (H) 17 e che GM-CSF ha avuto un ruolo essenziale nel loro encephalitogenicity. I nostri risultati identificano un capo meccanismo che sottende l&#39;importante ruolo di IL-23 nelle malattie autoimmuni. 23 IL indotta da un ciclo di feedback positivo per cui GM-CSF secernuti dalle cellule T (H) 17 ha stimolato la produzione di IL-23 da presentanti l&#39;antigene delle cellule. Tale regolamento cross IL 23 e GM-CSF spiega il modello simile di resistenza per autoimmunit&agrave; quando entrambe le due citochine &egrave; assente e identifica le cellule T (H) 17 come una fonte fondamentale di GM-CSF in infiammazione autoimmune.

La encephalitogenicity delle cellule T (H) 17 &egrave; dipendente sulla produzione del - 1 e IL-23-indotta della citochina GM-CSF.

&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20; 17 (IL-17&#xFF09;-&#x751F;&#x4EA7;&#x8F85;&#x52A9; T &#x7EC6;&#x80DE; &#xFF08;T (H) 17 &#x5355;&#x5143;&#x683C;&#xFF09; &#x9700;&#x8981;&#x66B4;&#x9732;&#x4E8E;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-23 &#x6210;&#x4E3A; encephalitogenic&#xFF0C;&#x4F46;&#x4E0D;&#x662F;&#x77E5;&#x9053;&#x5176;&#x4E2D;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-23 &#x4FC3;&#x8FDB;&#x5176;&#x81F4;&#x75C5;&#x529B;&#x7684;&#x673A;&#x5236;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x53D1;&#x73B0;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-23 &#x8BF1;&#x5BFC;&#x7EC6;&#x80DE;&#x56E0;&#x5B50;&#x7C92;&#x7EC6;&#x80DE;-&#x5DE8;&#x566C;&#x7EC6;&#x80DE;&#x96C6;&#x843D;&#x523A;&#x6FC0;&#x56E0;&#x5B50; (GM-CSF) T (H) 17 &#x7EC6;&#x80DE;&#x751F;&#x4EA7;&#x548C; GM-CSF &#x5728;&#x5176; encephalitogenicity &#x4E86;&#x81F3;&#x5173;&#x91CD;&#x8981;&#x7684;&#x4F5C;&#x7528;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x7814;&#x7A76;&#x7ED3;&#x679C;&#x786E;&#x5B9A;&#x4E00;&#x4E2A;&#x4E3B;&#x8981;&#x7684;&#x673A;&#x5236;&#xFF0C;&#x662F;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-23 &#x5728;&#x81EA;&#x8EAB;&#x514D;&#x75AB;&#x6027;&#x75BE;&#x75C5;&#x4E2D;&#x7684;&#x91CD;&#x8981;&#x4F5C;&#x7528;&#x7684;&#x57FA;&#x7840;&#x3002;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-23 &#x5F15;&#x8D77;&#x79EF;&#x6781;&#x7684;&#x53CD;&#x9988;&#x56DE;&#x8DEF;&#x5373; GM-CSF &#x7531; T (H) 17 &#x7EC6;&#x80DE;&#x5206;&#x6CCC;&#x523A;&#x6FC0;&#x751F;&#x4EA7;&#x7684;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-23 &#x7684;&#x6297;&#x539F;&#x9012;&#x5448;&#x7EC6;&#x80DE;&#x3002;&#x8FD9;&#x79CD;&#x8DE8;&#x5E02;&#x76D1;&#x7BA1;&#x7684;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-23 &#x548C; GM-CSF &#x89E3;&#x91CA;&#x81EA;&#x8EAB;&#x514D;&#x75AB;&#x6297;&#x6027;&#x7684;&#x7C7B;&#x4F3C;&#x7684;&#x6A21;&#x5F0F;&#x65F6;&#x4E24;&#x4E2A;&#x7EC6;&#x80DE;&#x56E0;&#x5B50;&#x4E4B;&#x4E00;&#x662F;&#x7F3A;&#x5E2D;&#xFF0C;&#x6807;&#x8BC6; T (H) 17 &#x7EC6;&#x80DE;&#x4F5C;&#x4E3A; GM-CSF &#x5728;&#x81EA;&#x8EAB;&#x514D;&#x75AB;&#x6027;&#x708E;&#x75C7;&#x4E2D;&#x7684;&#x4E00;&#x4E2A;&#x91CD;&#x8981;&#x6765;&#x6E90;&#x3002;

T (H) 17 &#x7EC6;&#x80DE;&#x7684; encephalitogenicity &#x662F;&#x4F9D;&#x8D56;&#x7EC6;&#x80DE;&#x56E0;&#x5B50; GM-CSF &#x7684; IL-1 &#x548C;&#x767D;&#x4ECB;&#x7D20;-23-&#x8BF1;&#x5BFC;&#x751F;&#x4EA7;&#x3002;

Interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) require exposure to IL-23 to become encephalitogenic, but the mechanism by which IL-23 promotes their pathogenicity is not known. Here we found that IL-23 induced production of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) in T(H)17 cells and that GM-CSF had an essential role in their encephalitogenicity. Our findings identify a chief mechanism that underlies the important role of IL-23 in autoimmune diseases. IL-23 induced a positive feedback loop whereby GM-CSF secreted by T(H)17 cells stimulated the production of IL-23 by antigen-presenting cells. Such cross-regulation of IL-23 and GM-CSF explains the similar pattern of resistance to autoimmunity when either of the two cytokines is absent and identifies T(H)17 cells as a crucial source of GM-CSF in autoimmune inflammation.

The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF.

L&#x26;#39;interleukine 17 (IL-17) de production de lymphocytes T auxiliaires (T (H) 17 cellules) n&#xE9;cessitent une exposition &#xE0; l&#x26;#39;IL-23 de devenir enc&#xE9;phalitog&#xE8;ne, mais le m&#xE9;canisme par lequel l&#x26;#39;IL-23 favorise leur pathog&#xE9;nicit&#xE9; n&#x26;#39;est pas connue. Ici nous avons constat&#xE9; que l&#x26;#39;IL-23 induit la production de la cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) dans T (H) 17 cellules et que le GM-CSF a un r&#xF4;le essentiel dans leur encephalitogenicity. Nos r&#xE9;sultats permettent d&#x26;#39;identifier un m&#xE9;canisme g&#xE9;n&#xE9;ral qui sous-tend le r&#xF4;le important de l&#x26;#39;IL-23 dans les maladies auto-immunes. IL-23 induit une boucle de r&#xE9;troaction positive selon laquelle GM-CSF s&#xE9;cr&#xE9;t&#xE9;e par T (H) 17 cellules a stimul&#xE9; la production d&#x26;#39;IL-23 par cellules pr&#xE9;sentatrices d&#x26;#39;antig&#xE8;ne. Cette r&#xE9;gulation crois&#xE9;e de l&#x26;#39;IL-23 et GM-CSF explique le sch&#xE9;ma semblable de la r&#xE9;sistance &#xE0; l&#x26;#39;auto-immunit&#xE9; lorsque l&#x26;#39;un des deux cytokines est absent et identifie T (H) 17 cellules en tant que source essentielle de GM-CSF dans l&#x26;#39;inflammation auto-immune.

Le Encephalitogenicity de T (H) 17 cellules d&#xE9;pend de l&#x26;#39;IL-1-et IL-23 induit la production de la cytokine GM-CSF

Interleukin 17 (IL-17)-Herstellung von T-Helferzellen (T (H) 17-Zellen) erfordern Exposition gegen&uuml;ber IL-23, Encephalitogenic zu werden, aber der Mechanismus, durch den IL-23 ihre Pathogenit&auml;t f&ouml;rdert, ist nicht bekannt. Hier fanden wir, dass IL-23 Herstellung von der Cytokine Granulozyten-Makrophagen-Kolonie-stimulierende Faktor (GM-CSF) in T (H) 17-Zellen induziert und GM-CSF eine wesentliche Rolle in ihren Encephalitogenicity hatte. Unsere Erkenntnisse identifizieren Chef-Mechanismus, der die wichtige Rolle der IL-23 bei Autoimmunerkrankungen zugrunde liegt. IL-23 induzierte eine positiven Feedback-Schleife, wobei GM-CSF abgesondert durch T (H) 17-Zellen die Produktion von IL-23 von Antigen-pr&auml;sentierenden stimuliert, Zellen. Solche Kreuz-Regelung der IL-23 und GM-CSF erkl&auml;rt das &auml;hnliche Muster des Widerstands gegen die Autoimmunit&auml;t, wenn entweder zwei Zytokine fehlt und dass T (H) 17-Zellen eine entscheidende Quelle der GM-CSF in autoimmune Entz&uuml;ndung.

Die Encephalitogenicity T (H) 17-Zellen ist abh&auml;ngig von IL - 1- und IL-23-induzierte Produktion von Zytokin GM-CSF.

&#x30A4;&#x30F3;&#x30BF;&#x30FC;&#x30ED;&#x30A4;&#x30AD;&#x30F3;17&#xFF08;IL-17&#xFF09;&#x7523;&#x751F;&#x30D8;&#x30EB;&#x30D1;&#x30FC;T&#x7D30;&#x80DE;&#xFF08;T&#xFF08;H&#xFF09;17&#x7D30;&#x80DE;&#xFF09;&#x306F;IL-23&#x3078;&#x306E;&#x66B4;&#x9732;&#x8133;&#x708E;&#x306B;&#x306A;&#x308B;&#x3053;&#x3068;&#x304C;&#x3001;IL-23&#x306F;&#x3001;&#x305D;&#x308C;&#x3089;&#x306E;&#x75C5;&#x539F;&#x6027;&#x304C;&#x77E5;&#x3089;&#x308C;&#x3066;&#x3044;&#x306A;&#x3044;&#x4FC3;&#x9032;&#x3059;&#x308B;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x304C;&#x5FC5;&#x8981;&#x306B;&#x306A;&#x308A;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;T&#x306E;&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;&#x9846;&#x7C92;&#x7403;&#x30DE;&#x30AF;&#x30ED;&#x30D5;&#x30A1;&#x30FC;&#x30B8;&#x30B3;&#x30ED;&#x30CB;&#x30FC;&#x523A;&#x6FC0;&#x56E0;&#x5B50;&#xFF08;GM-CSF&#xFF09;&#xFF08;H&#xFF09;17&#x7D30;&#x80DE;&#x306E;IL-23&#x8A98;&#x5C0E;&#x751F;&#x7523;&#x3059;&#x308B;&#x3053;&#x3068;&#x3068;GM-CSF&#x306F;&#x305D;&#x306E;encephalitogenicity&#x306B;&#x91CD;&#x8981;&#x306A;&#x5F79;&#x5272;&#x3092;&#x6301;&#x3063;&#x3066;&#x3044;&#x305F;&#x3053;&#x3068;&#x304C;&#x5206;&#x304B;&#x3063;&#x305F;&#x3002;&#x6211;&#x3005;&#x306E;&#x8ABF;&#x67FB;&#x7D50;&#x679C;&#x306F;&#x3001;&#x81EA;&#x5DF1;&#x514D;&#x75AB;&#x75BE;&#x60A3;&#x306B;&#x304A;&#x3051;&#x308B;IL-23&#x306E;&#x91CD;&#x8981;&#x306A;&#x5F79;&#x5272;&#x3092;&#x6839;&#x5E95;&#x30C1;&#x30FC;&#x30D5;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x3092;&#x8B58;&#x5225;&#x3057;&#x307E;&#x3059;&#x3002; T&#xFF08;H&#xFF09;17&#x7D30;&#x80DE;&#x306B;&#x3088;&#x308B;GM-CSF&#x5206;&#x6CCC;&#x6297;&#x539F;&#x63D0;&#x793A;&#x7D30;&#x80DE;&#x306B;&#x3088;&#x308B;IL-23&#x306E;&#x7523;&#x751F;&#x3092;&#x523A;&#x6FC0;&#x3059;&#x308B;&#x3053;&#x3068;&#x306B;&#x3088;&#x308A;IL-23&#x306F;&#x3001;&#x6B63;&#x306E;&#x30D5;&#x30A3;&#x30FC;&#x30C9;&#x30D0;&#x30C3;&#x30AF;&#x30EB;&#x30FC;&#x30D7;&#x3092;&#x8A98;&#x767A;&#x3057;&#x305F;&#x3002; 2&#x3064;&#x306E;&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;&#x306E;&#x3044;&#x305A;&#x308C;&#x304B;&#x304C;&#x5B58;&#x5728;&#x305B;&#x305A;&#x3001;T&#xFF08;H&#xFF09;&#x81EA;&#x5DF1;&#x514D;&#x75AB;&#x6027;&#x708E;&#x75C7;&#x306B;&#x304A;&#x3051;&#x308B;GM-CSF&#x306E;&#x91CD;&#x8981;&#x306A;&#x30BD;&#x30FC;&#x30B9;&#x3068;&#x3057;&#x3066;17&#x7D30;&#x80DE;&#x3092;&#x8B58;&#x5225;&#x3059;&#x308B;&#x3068;&#x304D;&#x306B;IL-23&#x3068;GM-CSF&#x306E;&#x3088;&#x3046;&#x306A;&#x30AF;&#x30ED;&#x30B9;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x306F;&#x3001;&#x81EA;&#x5DF1;&#x514D;&#x75AB;&#x306B;&#x62B5;&#x6297;&#x6027;&#x306E;&#x540C;&#x69D8;&#x306E;&#x30D1;&#x30BF;&#x30FC;&#x30F3;&#x3092;&#x8AAC;&#x660E;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

T&#xFF08;H&#xFF09;17&#x7D30;&#x80DE;&#x306E;Encephalitogenicity&#x306F;&#x3001;&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;GM-CSF&#x306E;IL-1&#x3084;IL-23&#x8A98;&#x5C0E;&#x751F;&#x7523;&#x306B;&#x4F9D;&#x5B58;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;

17 &#xC778;&#xD130; &#xB8E8; &#xD0A8; (IL-17)-&#xC0DD;&#xC0B0; &#xBCF4;&#xC870; T &#xC138;&#xD3EC; (T (H) 17 &#xC140;) IL-23 encephalitogenic, &#xB178;&#xCD9C;&#xC774; &#xD544;&#xC694; &#xD558;&#xC9C0;&#xB9CC; IL 23 &#xADF8;&#xB4E4;&#xC758; pathogenicity&#xC744; &#xCD09;&#xC9C4; &#xD558;&#xB294; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xC54C; &#xC218; &#xC5C6;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC5EC;&#xAE30; &#xC6B0;&#xB9AC;&#xAC00; &#xBC1C;&#xACAC; IL 23&#xB294; cytokine granulocyte macrophage &#xCF5C;&#xB85C; &#xB2C8; &#xC790;&#xADF9; &#xC778;&#xC790; (GM-CSF) T (H) 17 &#xC140;&#xC5D0;&#xC11C;&#xC758; &#xC0DD;&#xC0B0;&#xC744; &#xC720;&#xB3C4; &#xD558; &#xACE0; GM-CSF &#xADF8;&#xB4E4;&#xC758; encephalitogenicity&#xC5D0; &#xC911;&#xC694; &#xD55C; &#xC5ED;&#xD560;&#xC744; &#xD588;&#xB2E4;. &#xC6B0;&#xB9AC;&#xC758; &#xC5F0;&#xAD6C; &#xACB0;&#xACFC; &#xBA74;&#xC5ED; &#xC9C8;&#xD658;&#xC5D0;&#xC11C; IL-23&#xC758; &#xC911;&#xC694; &#xD55C; &#xC5ED;&#xD560;&#xC758; &#xAE30;&#xCD08;&#xAC00; &#xB418;&#xB294; &#xC8FC;&#xC694;&#xD55C; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xC2DD;&#xBCC4; &#xD569;&#xB2C8;&#xB2E4;. IL 23 GM-CSF T (H) 17 &#xC138;&#xD3EC;&#xC5D0; &#xC758;&#xD574; &#xBD84; &#xBE44; &#xD56D; &#xC6D0;&#xC744; &#xC81C;&#xC2DC; &#xD558; &#xC5EC; IL 23&#xC758; &#xC0DD;&#xC0B0;&#xC744; &#xC790;&#xADF9; &#xD558;&#xB294; &#xBA74; &#xAE0D;&#xC815;&#xC801;&#xC778; &#xD53C;&#xB4DC;&#xBC31; &#xB8E8;&#xD504;&#xB97C; &#xC774;&#xC6A9;&#xD55C; &#xC140;. IL 23 GM-CSF&#xC758; &#xD06C;&#xB85C;&#xC2A4; &#xADDC;&#xC81C; &#xAC19;&#xC740; &#xB450; cytokines&#xC758; &#xACB0; &#xC11D; &#xD558;&#xB294; &#xACBD;&#xC6B0; &#xC790;&#xAE30; &#xBA74;&#xC5ED; &#xC5FC;&#xC99D;&#xC5D0; GM-CSF&#xC758; &#xC911;&#xC694; &#xD55C; &#xC18C;&#xC2A4;&#xB85C; T (H) 17 &#xC140; &#xC2DD;&#xBCC4; autoimmunity &#xC800;&#xD56D;&#xC758; &#xBE44;&#xC2B7;&#xD55C; &#xD328;&#xD134;&#xC5D0; &#xC124;&#xBA85; &#xD569;&#xB2C8;&#xB2E4;.

T (H) 17 &#xC140;&#xC758; encephalitogenicity&#xC758; GM-CSF cytokine &#xC0DD;&#xC0B0; IL-1&#xACFC; &#xC77C;&#xB9AC;&#xB178;&#xC774;-23-&#xC720;&#xB3C4;&#xC5D0; &#xB530;&#xB77C; &#xB2EC;&#xB77C; &#xC9D1;&#xB2C8;&#xB2E4;.

La interleucina 17 (IL-17) que producen c&#xE9;lulas T cooperadoras (T (H) 17 c&#xE9;lulas) requieren la exposici&#xF3;n a IL-23 para convertirse en encefalitog&#xE9;nico, pero el mecanismo por el cual la IL-23 promueve su patogenicidad no se conoce. Aqu&#xED; se encontr&#xF3; que la IL-23 producci&#xF3;n inducida de la citoquina de granulocitos y macr&#xF3;fagos factor estimulante de colonias (GM-CSF) en T (H) 17 c&#xE9;lulas y que el GM-CSF ten&#xED;an un papel esencial en su encephalitogenicity. Nuestros resultados identifican un mecanismo principal que subyace en el importante papel de la IL-23 en las enfermedades autoinmunes. IL-23 induce un bucle de retroalimentaci&#xF3;n positiva por el que el GM-CSF secretado por T (H) 17 c&#xE9;lulas estimul&#xF3; la producci&#xF3;n de IL-23 mediante la presentaci&#xF3;n de ant&#xED;geno-c&#xE9;lulas. Esta cruz de regulaci&#xF3;n de la IL-23 y GM-CSF explica el patr&#xF3;n de resistencia similar a la autoinmunidad cuando cualquiera de las dos citoquinas est&#xE1; ausente y se identifica T (H) 17 c&#xE9;lulas como una fuente crucial de GM-CSF en la inflamaci&#xF3;n autoinmune.

El Encephalitogenicity de T (H) 17 c&#xE9;lulas depende de la IL-1 e IL-23 inducida por la producci&#xF3;n de la citocina GM-CSF

Muscle-invasive forms of urothelial carcinomas are responsible for most mortality in bladder cancer. Finding new treatments for invasive bladder tumours requires adequate animal models to decipher the mechanisms of progression, in particular the way tumours interact with their microenvironment. Herein, using the murine bladder tumour cell line MB49 and its more aggressive variant MB49-I, we demonstrate that the adaptive immune system efficiently limits progression of MB49, whereas MB49-I has lost tumour antigens and is insensitive to adaptive immune responses. Furthermore, we unravel a parallel mechanism developed by MB49-I to subvert its environment: de novo secretion of the proteoglycan decorin. We show that decorin overexpression in the MB49/MB49-I model is required for efficient progression, by promoting angiogenesis and tumour cell invasiveness. Finally, we show that these results are relevant to muscle-invasive human bladder carcinomas, which overexpress decorin together with angiogenesis- and adhesion/migration-related genes, and that decorin overexpression in the human bladder carcinoma cell line TCCSUP is required for efficient invasiveness in vitro. We thus propose decorin as a new therapeutic target for these aggressive tumours.

An essential role for decorin in bladder cancer invasiveness.

IL-17-secreting CD8(+) T cells (Tc17 cells) have been implicated in immunity to infections, cancer, and autoimmune diseases. Thus far, studies on Tc17 cells have primarily investigated their development from naïve precursors, while the biology of committed Tc17 cells has been less characterized, in particular during the effector phase of immune responses. IL-27 is an important regulator of inflammation through the induction of regulatory Tr1 cells, as well as a suppressor of Th17-cell development. IL-27 suppresses the development of Tc17 cells, but its effects on committed Tc17 cells are unknown. Here we demonstrate that even though IL-27 completely inhibited the development of C57BL/6 mouse Tc17 cells, it had little effect on previously committed Tc17 cells. Although committed Tc17 cells were capable of responding to IL-27, it had no effect on expression of RORγt and RORα, or production of various cytokines. Committed Tc17 cells did not express granzyme B and lacked cytotoxicity in vitro, features that remained unaltered by IL-27 treatment. Nonetheless, they efficiently induced diabetes, irrespective of treatment with IL-27 prior to transfer into RIP-mOVA mice. These findings suggest that use of IL-27 to modulate autoimmune diseases might have limited therapeutic efficacy if autoaggressive Tc17 cells have already developed.

Committed Tc17 cells are phenotypically and functionally resistant to the effects of IL-27.

One major challenge in multiple sclerosis is to understand the cellular and molecular mechanisms leading to disease severity progression. The recently demonstrated correlation between disease severity and remyelination emphasizes the importance of identifying factors leading to a favourable outcome. Why remyelination fails or succeeds in multiple sclerosis patients remains largely unknown, mainly because remyelination has never been studied within a humanized pathological context that would recapitulate major events in plaque formation such as infiltration of inflammatory cells. Therefore, we developed a new paradigm by grafting healthy donor or multiple sclerosis patient lymphocytes in the demyelinated lesion of nude mice spinal cord. We show that lymphocytes play a major role in remyelination whose efficacy is significantly decreased in mice grafted with multiple sclerosis lymphocytes compared to those grafted with healthy donors lymphocytes. Mechanistically, we demonstrated in vitro that lymphocyte-derived mediators influenced differentiation of oligodendrocyte precursor cells through a crosstalk with microglial cells. Among mice grafted with lymphocytes from different patients, we observed diverse remyelination patterns reproducing for the first time the heterogeneity observed in multiple sclerosis patients. Comparing lymphocyte secretory profile from patients exhibiting high and low remyelination ability, we identified novel molecules involved in oligodendrocyte precursor cell differentiation and validated CCL19 as a target to improve remyelination. Specifically, exogenous CCL19 abolished oligodendrocyte precursor cell differentiation observed in patients with high remyelination pattern. Multiple sclerosis lymphocytes exhibit intrinsic capacities to coordinate myelin repair and further investigation on patients with high remyelination capacities will provide new pro-regenerative strategies.

Article	Year
A three-dimensional tumor cell defect in activating autologous CTLs is associated with inefficient antigen presentation correlated with heat shock protein-70 down-regulation. Cancer research\| PubMed ID: 12839959	2003
New insights into cell responses involved in experimental autoimmune encephalomyelitis and multiple sclerosis. Immunology letters\| PubMed ID: 15585303	2005
Diversified serum IgG response involving non-myelin CNS proteins during experimental autoimmune encephalomyelitis. Journal of neuroimmunology\| PubMed ID: 16893572	2006
Changes in self-reactive IgG antibody repertoire after treatment of experimental autoimmune encephalomyelitis with anti-allergic drugs. Journal of neuroimmunology\| PubMed ID: 17097744	2007
Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nature immunology\| PubMed ID: 17994023	2007
IL-23 drives pathogenic IL-17-producing CD8+ T cells. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 19380776	2009
Differential effect of IL-27 on developing versus committed Th17 cells. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 19786534	2009
Current views on the roles of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology\| PubMed ID: 20107924	2010
The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nature immunology\| PubMed ID: 21516111	2011
An essential role for decorin in bladder cancer invasiveness. EMBO molecular medicine\| PubMed ID: 24142880	2013
Committed Tc17 cells are phenotypically and functionally resistant to the effects of IL-27. European journal of immunology\| PubMed ID: 25070084	2014
Adaptive human immunity drives remyelination in a mouse model of demyelination. Brain : a journal of neurology\| PubMed ID: 28334918	2017

Mohamed El-Behi

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