new-tools-to-expand-regulatory-t-cells-from-hiv-1-infected-individuals

New Tools to Expand Regulatory T Cells from HIV-1-infected Individuals

CD4+ Regulatory T cells (Tregs) are potent immune modulators and serve an important function in human immune homeostasis. Depletion of Tregs has led to ...

Ragon Institute of MGH, MIT, and Harvard

Although clinical trials using anti-CD40L mAb have been halted, blockade of CD40-CD40L interactions has given promising results in rodent and nonhuman primate models. Recently, new insights into the consequences of blocking CD40-CD40L interactions have led to the possibility of overcoming the thromboembolic complications previously associated with this strategy and may pave the way for successful tolerance induction. This mini review will address the issues relating to CD40-CD40L blockade in allotransplantation.

Promises and obstacles for the blockade of CD40-CD40L interactions in allotransplantation.

Bien que les essais cliniques utilisant des anti-CD40L mAb ont &eacute;t&eacute; interrompus, blocus des interactions CD40-CD40L a donn&eacute; des r&eacute;sultats prometteurs dans les rongeurs et les primates mod&egrave;les. R&eacute;cemment, les nouvelles connaissances sur les cons&eacute;quences du blocage des interactions CD40-CD40L ont conduit &agrave; la possibilit&eacute; de surmonter les complications thrombo-emboliques pr&eacute;c&eacute;demment associ&eacute;es &agrave; cette strat&eacute;gie et pourraient ouvrir la voie pour l&#39;induction de la tol&eacute;rance r&eacute;ussie. Cette mini revue abordera les questions relatives au blocage de CD40-CD40L &agrave; allotransplantation.

Promesses et obstacles pour le blocage des interactions CD40-CD40L &agrave; allotransplantation.

Sebbene studi clinici utilizzando mAb anti-CD40L sono stati fermati, blocco di interazione CD40-CD40L ha dato risultati promettenti in roditori e nonhuman primate modelli. Di recente, nuove intuizioni le conseguenze del blocco CD40-CD40L interazioni hanno portato alla possibilit&agrave; di superare le complicanze tromboemboliche in precedenza associate a questa strategia e possono spianare la strada per l&#39;induzione di tolleranza di successo. Questa mini recensione affronter&agrave; le questioni relative al blocco CD40-CD40L in allotransplantation.

Promesse e gli ostacoli per il blocco delle interazioni CD40-CD40L in allotransplantation.

Malgr&eacute; les preuves s&#39;accumulent pour l&#39;importance d&#39;&eacute;tendu CD8 des lymphocytes T r&eacute;gulateurs (Tregs) tol&eacute;rant aux rongeurs et immunosuppression gratuite greff&eacute;s, m&eacute;canismes sous-jacents CD8 tol&eacute;rance induite par Treg restent floues. En utilisant un mod&egrave;le de tol&eacute;rance de transplantation m&eacute;di&eacute;e par CD8 Tregs apr&egrave;s un traitement de CD40Ig chez le rat, dans cette &eacute;tude, nous montrons que l&#39;accumulation des tol&eacute;rog&egrave;ne CD8 Tregs et plasmacytoides cellules dendritiques (PDC) dans une allogreffe et rate mais pas de ganglions lymphatiques &eacute;tait li&eacute;e &agrave; l&#39;induction de la tol&eacute;rance chez les receveurs d&#39;une allogreffe vascularis&eacute;e. PDC induit pr&eacute;f&eacute;rentiellement tol&eacute;rog&egrave;ne CD8 Tregs pour supprimer l&#39;effecteur de CD4 + cellules r&eacute;ponses aux premiers et les donateurs Ags in vitro. Lorsque tol&eacute;rog&egrave;ne Tregs CD8 n&#39;&eacute;taient pas en contact avec des CD4 + les cellules effectrices, r&eacute;pression a &eacute;t&eacute; v&eacute;hicul&eacute;e par IDO. Entrer en contact avec les cellules effectrices CD4 a abouti &agrave; des m&eacute;canismes de rechange suppressives impliquant l&#39;IFN-gamma et fibroleukin-2. In vivo, les IDO et IFN-gamma participaient &agrave; induction de la tol&eacute;rance, sugg&eacute;rant que le contact avec les cellules effectrices CD4 + est crucial pour moduler la fonction CD8 Tregs in vivo. En conclusion, CD8 Tregs et PDC interactions ont &eacute;t&eacute; n&eacute;cessaires &agrave; la suppression des cellules T CD4 + et des m&eacute;canismes diff&eacute;rents impliqu&eacute;s modul&eacute;e par la pr&eacute;sence de cellule de contact entre les CD4 + CD8 Tregs et PDC cellules effectrices.

M&eacute;canisme et localisation des lymphocytes T r&eacute;gulateurs de CD8 dans un coeur mod&egrave;le de tol&eacute;rance de la greffe.

Despite accumulating evidence for the importance of allospecific CD8(+) regulatory T cells (Tregs) in tolerant rodents and free immunosuppression transplant recipients, mechanisms underlying CD8(+) Treg-mediated tolerance remain unclear. By using a model of transplantation tolerance mediated by CD8(+) Tregs following CD40Ig treatment in rats, in this study, we show that the accumulation of tolerogenic CD8(+) Tregs and plasmacytoid dendritic cells (pDCs) in allograft and spleen but not lymph nodes was associated with tolerance induction in vascularized allograft recipients. pDCs preferentially induced tolerogenic CD8(+) Tregs to suppress CD4(+) effector cells responses to first-donor Ags in vitro. When tolerogenic CD8(+) Tregs were not in contact with CD4(+) effector cells, suppression was mediated by IDO. Contact with CD4(+) effector cells resulted in alternative suppressive mechanisms implicating IFN-gamma and fibroleukin-2. In vivo, both IDO and IFN-gamma were involved in tolerance induction, suggesting that contact with CD4(+) effector cells is crucial to modulate CD8(+) Tregs function in vivo. In conclusion, CD8(+) Tregs and pDCs interactions were necessary for suppression of CD4(+) T cells and involved different mechanisms modulated by the presence of cell contact between CD8(+) Tregs, pDCs, and CD4(+) effector cells.

Mechanism and localization of CD8 regulatory T cells in a heart transplant model of tolerance.

Nonostante ad accumulare prove per l&#39;importanza del allospecific cellule cellule T regolatorie (Tregs) in roditori tollerante e immunosoppressione libero trapianto destinatari, meccanismi sottostanti cellule Treg-mediata tolleranza rimangono poco chiari. Utilizzando un modello di tolleranza di trapianto mediata da cellule Tregs dopo il trattamento di CD40Ig in ratti, in questo studio, ci mostrano che l&#39;accumulo di cellule Tregs e plasmacytoid cellule dendritiche tollerogeniche (pDCs) nel allograft e milza ma non i linfonodi &egrave; stato associato con induzione di tolleranza in destinatari allotrapianto vascolarizzato. PDC preferenzialmente indotta tollerogeniche cellule Tregs a sopprimere CD4(+) effector cells responses to primo donatore Ags in vitro. Quando tollerogeniche cellule Tregs non erano a contatto con cellule effettrici CD4(+), soppressione fu mediata da IDO. Contatto con cellule effettrici CD4(+) portate a meccanismi alternativi soppressive implicando IFN-gamma e fibroleukin-2. In vivo, sia IDO e IFN-gamma sono stati coinvolti nell&#39;induzione di tolleranza, suggerendo che il contatto con cellule effettrici CD4(+) &egrave; fondamentale per modulare la funzione di cellule Tregs in vivo. In conclusione, cellule Tregs e PDC interazioni erano necessarie per la soppressione delle cellule T CD4(+) e coinvolti diversi meccanismi modulata dalla presenza di cellule contatto tra cellule Tregs, PDC e CD4(+) cellule effettrici.

Meccanismo e la localizzazione delle cellule T regolatorie CD8 in un cuore trapianto modello di tolleranza.

Regulatory T cell frequencies do not correlate with breadth or magnitude of HIV-1-specific T cell responses.

Fr&eacute;quences de lymphocytes T r&eacute;gulateurs ne concordent pas avec la largeur ou l&#39;ampleur des lymphocytes T sp&eacute;cifiques au VIH-1.

Frequenze di cellule T regolatori non correlare con ampiezza o grandezza di HIV-1-specifiche risposte delle cellule T.

Regulatory T cells (Tregs) are potent immune modulators, but their role in human immunodeficiency virus type 1 (HIV-1) pathogenesis remains poorly understood. We performed a detailed analysis of the frequency and function of Tregs in a large cohort of HIV-1-infected individuals and HIV-1 negative controls. While HIV "elite controllers" and uninfected individuals had similar Treg numbers and frequencies, the absolute numbers of Tregs declined in blood and gut-associated lymphoid tissue in patients with chronic progressive HIV-1 infection. Despite quantitative changes in Tregs, HIV-1 infection was not associated with an impairment of ex vivo suppressive function of flow-sorted Tregs in both HIV controllers and untreated chronic progressors.

Preserved function of regulatory T cells in chronic HIV-1 infection despite decreased numbers in blood and tissue.

Les lymphocytes T r&eacute;gulateurs (Tregs) sont des immunomodulateurs puissants, mais leur r&ocirc;le dans le virus de l&#39;immunod&eacute;ficience humaine de type 1 (VIH-1) demeure de pathog&eacute;n&egrave;se mal compris. Nous avons effectu&eacute; une analyse d&eacute;taill&eacute;e de la fr&eacute;quence et de la fonction des Tregs dans une grande cohorte de personnes infect&eacute;es par le VIH-1 et VIH-1 t&eacute;moins n&eacute;gatifs. Alors que les &laquo; Contr&ocirc;leurs d&#39;&eacute;lites &raquo; du VIH et des individus non infect&eacute;s ont des fr&eacute;quences et des num&eacute;ros de Treg semblable, le nombre absolu de Tregs a diminu&eacute; dans le sang et le tissu lympho&iuml;de associ&eacute; intestinale chez des patients pr&eacute;sentant une infection VIH-1 progressive chronique. Malgr&eacute; les changements quantitatifs en Tregs, infection &agrave; VIH-1 n&#39;&eacute;tait pas associ&eacute;e &agrave; une atteinte ex vivo fonction suppressive de Tregs flux-tri&eacute;s dans les contr&ocirc;leurs du VIH et des progresseurs chroniques non trait&eacute;es.

Conserv&eacute; la fonction des lymphocytes T r&eacute;gulateurs de l&#39;infection chronique par le VIH-1 Malgr&eacute; une diminution dans le sang et les tissus.

Cellule T regolatorie (Tregs) sono potenti modulatori immuni, ma il loro ruolo nel virus dell&#39;immunodeficienza umana tipo 1 (HIV-1) resti di patogenesi poco compreso. Abbiamo effettuato una dettagliata analisi della frequenza e la funzione di Tregs in un&#39;ampia coorte di individui infetti di HIV-1 e HIV-1 controlli negativi. Mentre l&#39;HIV &quot;elite controller&quot; e gli individui non infetti avevano Treg numeri e frequenze simili, il numero assoluto di Tregs diminuito nel sangue e tessuto linfoide intestinale nei pazienti con infezione da HIV-1 progressiva cronica. Malgrado i cambiamenti quantitativi in Tregs, infezione da HIV-1 non &egrave; stato associato a un danno dell&#39;ex vivo funzione soppressiva del flusso ordinato Tregs controller di HIV sia progressori croniche non trattate.

Conservata la funzione delle cellule T regolatorie nell&#39;infezione cronica da HIV-1, nonostante i numeri diminuiti nel sangue e nel tessuto.

T cell dysfunction in the presence of ongoing antigen exposure is a cardinal feature of chronic viral infections with persistent high viremia, including HIV-1. Although interleukin-10 (IL-10) has been implicated as an important mediator of this T cell dysfunction, the regulation of IL-10 production in chronic HIV-1 infection remains poorly understood. We demonstrated that IL-10 is elevated in the plasma of individuals with chronic HIV-1 infection and that blockade of IL-10 signaling results in a restoration of HIV-1-specific CD4 T cell proliferation, gamma interferon (IFN-Î³) secretion, and, to a lesser extent, IL-2 production. Whereas IL-10 blockade leads to restoration of IFN-Î³ secretion by HIV-1-specific CD4 T cells in all categories of subjects investigated, significant enhancement of IL-2 production and improved proliferation of CD4 T helper cells are restricted to viremic individuals. In peripheral blood mononuclear cells (PBMCs), this IL-10 is produced primarily by CD14(+) monocytes, but its production is tightly controlled by regulatory T cells (Tregs), which produce little IL-10 directly. When Tregs are depleted from PBMCs of viremic individuals, the effect of the IL-10 signaling blockade is abolished and IL-10 production by monocytes decreases, while the production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-Î±), increases. The regulation of IL-10 by Tregs appears to be mediated primarily by contact or paracrine-dependent mechanisms which involve IL-27. This work describes a novel mechanism by which regulatory T cells control IL-10 production and contribute to dysfunctional HIV-1-specific CD4 T cell help in chronic HIV-1 infection and provides a unique mechanistic insight into the role of regulatory T cells in immune exhaustion.

CD4+ CD25+ regulatory T cells impair HIV-1-specific CD4 T cell responses by upregulating interleukin-10 production in monocytes.

Dysfonction des cellules t en pr&eacute;sence de l&#39;exposition de l&#39;antig&egrave;ne en cours est une fonctionnalit&eacute; Cardinale des infections virales chroniques avec persistance une vir&eacute;mie &eacute;lev&eacute;e, y compris le VIH-1. Bien que l&#39;interleukine-10 (IL-10) a &eacute;t&eacute; mis en cause comme un m&eacute;diateur important de ce dysfonctionnement de la cellule T, la r&eacute;gulation de la production d&#39;IL-10 dans chronique HIV-1 infection reste mal comprise. Nous avons d&eacute;montr&eacute; que l&#39;IL-10 est &eacute;lev&eacute;e dans le plasma des individus pr&eacute;sentant une infection chronique du VIH-1 et que le blocage de l&#39;IL-10 r&eacute;sultats signalisation dans une restauration de la prolif&eacute;ration des cellules T CD4 sp&eacute;cifiques au VIH-1, la s&eacute;cr&eacute;tion d&#39;interf&eacute;ron (IFN-&gamma;) gamma et, dans une moindre mesure, la production de IL-2. Alors que le blocus de l&#39;IL-10 conduit &agrave; restauration de s&eacute;cr&eacute;tion d&#39;IFN-&gamma; par des cellules T CD4 sp&eacute;cifiques au VIH-1 dans toutes les cat&eacute;gories de sujets &eacute;tudi&eacute;s, une am&eacute;lioration significative de la production IL-2 et am&eacute;lioration de prolif&eacute;ration des cellules T CD4 auxiliaires sont limit&eacute;s aux personnes vir&eacute;miques. Dans les cellules mononucl&eacute;aires du sang p&eacute;riph&eacute;rique (PBMC), cet IL-10 est produite principalement par les monocytes CD14(+), mais sa production est &eacute;troitement contr&ocirc;l&eacute;e par les lymphocytes T r&eacute;gulateurs (Tregs), qui produisent peu d&#39;IL-10 directement. Lorsque Tregs sont &eacute;puis&eacute;es de PBMC de personnes vir&eacute;miques, l&#39;effet de l&#39;IL-10 signalisation blocus est abolie et la production d&#39;IL-10 par des diminutions de monocytes, tandis que la production de cytokines pro-inflammatoires, telles que le facteur de n&eacute;crose tumorale alpha (TNF-&alpha;), augmente. Le r&egrave;glement d&#39;IL-10 par Tregs semble &ecirc;tre m&eacute;di&eacute;es principalement par contact ou paracrine d&eacute;pendant des m&eacute;canismes qui impliquent des IL-27. Ce travail d&eacute;crit un nouveau m&eacute;canisme par lequel des cellules T r&eacute;gulatrices contr&ocirc;lent la production d&#39;IL-10 et contribuent &agrave; dysfonctionnel aide de cellules T CD4 sp&eacute;cifiques au VIH-1 dans l&#39;infection chronique par le VIH-1 et jette un regard m&eacute;caniste unique sur le r&ocirc;le des lymphocytes T r&eacute;gulateurs d&#39;&eacute;puisement immunitaire.

Lymphocytes T r&eacute;gulateurs CD4 + CD25 + alt&eacute;rer les lymphocytes T CD4 sp&eacute;cifiques au VIH-1 par la production d&#39;interleukin-10 cytoprotectrices dans les monocytes.

Disfunzione delle cellule t in presenza di esposizione dell&#39;antigene in corso &egrave; una caratteristica cardinale di infezioni virali croniche con viremia elevata persistente, tra cui l&#39;HIV-1. Sebbene interleukin-10 (IL-10) &egrave; stato implicato come un mediatore importante di questa disfunzione delle cellule T, la regolazione della produzione di IL-10 in resti di infezione HIV-1 cronici mal capito. Abbiamo dimostrato che IL-10 &egrave; elevata nel plasma di individui con infezione cronica da HIV-1 e quel blocco di IL-10 segnalazione risultati in un restauro di proliferazione delle cellule T CD4 HIV-1-specifiche, la secrezione di gamma interferone (IFN-&gamma;) e, in misura minore, produzione IL-2. Considerando che IL-10 blocco porta a restauro di secrezione di IFN-&gamma; da parte delle cellule T CD4 specifici dell&#39;HIV-1 in tutte le categorie di soggetti indagati, significativo aumento della produzione di IL-2 e maggiore proliferazione delle cellule helper CD4 T sono limitati ai soggetti viremici. In cellule mononucleate di sangue periferico (PBMCs), questo IL-10 &egrave; prodotto principalmente da CD14(+) monociti, ma la produzione &egrave; strettamente controllata da cellule di T regolatorie (Tregs), che producono direttamente IL piccolo-10. Quando Tregs sono esaurite da PBMCs di soggetti viremici, aumenta l&#39;effetto di IL-10 segnalazione blocco &egrave; abolito e di produzione di IL-10 da diminuzioni di monociti, mentre la produzione di citochine proinfiammatorie, come fattore di necrosi tumorale alfa (TNF-&alpha;). Il regolamento di IL-10 da Tregs sembra essere mediate principalmente da contatto o paracrina-dipendente meccanismi che coinvolgono IL 27. Questo lavoro descrive un meccanismo romanzo che cellule T regolatorie controllano la produzione di IL-10 e contribuiscono a disfunzionali aiuto di cellule T CD4 specifici dell&#39;HIV-1 nell&#39;infezione cronica da HIV-1 e fornisce una visione meccanicistica unica il ruolo delle cellule T regolatorie in esaurimento immunitario.

CD4 + CD25 + cellule T regolatorie compromettere le risposte delle cellule T CD4 HIV-1-specifiche di produzione di interleuchina-10 upregulating nei monociti.

T cell immunoglobulin and mucin domainâ€“containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells during infection with HIV-1 and hepatitis C virus. By contrast, Tim-3 expression and function are defective in multiple human autoimmune diseases. However, the molecular mechanisms modulating Tim-3 function are not well understood. Here we show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds to, and represses the function of, Tim-3. Bat3 protects T helper type 1 (TH1) cells from galectin-9â€“mediated cell death and promotes both proliferation and proinflammatory cytokine production. Bat3-deficient T cells have elevated expression of exhaustion-associated molecules such as Tim-3, Lag3, Prdm1 and Pbx3, and Bat3 knockdown in myelin-antigenâ€“specific CD4+ T cells markedly inhibits the development of experimental autoimmune encephalomyelitis while promoting the expansion of a dysfunctional Tim-3hi, interferon-Î³ (IFN-Î³)loCD4+ cell population. Furthermore, expression of Bat3 is reduced in exhausted Tim-3+ T cells from mouse tumors and HIV-1â€“infected individuals. These data indicate that Bat3 acts as an inhibitor of Tim-3â€“dependent exhaustion and cell death. Bat3 may thus represent a viable therapeutic target in autoimmune disorders, chronic infections and cancers.

Bat3 promotes T cell responses and autoimmunity by repressing Tim-3â€“mediated cell death and exhaustion.

Lymphocytes t immunoglobuline et mucine domain&ndash;containing 3 (Tim-3) est un r&eacute;cepteur inhibiteur qui est exprim&eacute; sur les cellules T &eacute;puis&eacute;s au cours de l&#39;infection par le virus VIH-1 et l&#39;h&eacute;patite C. En revanche, la fonction et l&#39;expression de Tim-3 sont d&eacute;fectueuses dans plusieurs maladies auto-immunes humaines. Cependant, les m&eacute;canismes mol&eacute;culaires modulant Tim-3 fonction ne sont pas bien compris. Nous d&eacute;montrons cet antig&egrave;ne leucocytaire humain B (HLA-B)-transcription associ&eacute; 3 (Bat3) se lie &agrave; et r&eacute;prime la fonction de, Tim-3. Bat3 prot&egrave;ge T helper de type 1 (TH1) les cellules de la galectine-9&ndash;mediated la mort cellulaire et favorise la production de cytokine prolif&eacute;ration tant pro-inflammatoires. Cellules de T Bat3 d&eacute;ficientes &eacute;lev&eacute;s d&#39;expression des mol&eacute;cules d&#39;&eacute;puisement-associ&eacute;s tels que Tim-3, Lag3, Prdm1 et Pbx3, et Bat3 knockdown dans les cellules T CD4 + la my&eacute;line-antigen&ndash;specific nettement inhibe le d&eacute;veloppement de l&#39;enc&eacute;phalomy&eacute;lite allergique exp&eacute;rimentale tout en favorisant l&#39;expansion d&#39;un Tim-3hi dysfonctionnel, population de l&#39;interf&eacute;ron-&gamma; (IFN-&gamma;) loCD4 + cellules. En outre, expression de Bat3 est r&eacute;duite &agrave; Tim &eacute;puis&eacute;-3 + T cellules des tumeurs de souris et des personnes VIH-1&ndash;infected. Ces donn&eacute;es indiquent que Bat3 agit comme un inhibiteur de Tim-3&ndash;dependent &eacute;puisement et la mort cellulaire. Bat3 repr&eacute;senteraient donc une cible th&eacute;rapeutique viable dans les maladies auto-immunes, les cancers et les infections chroniques.

Bat3 promeut des lymphocytes T et l&#39;auto-immunit&eacute; en r&eacute;primant l&#39;&eacute;puisement et la mort cellulaire Tim-3&ndash;mediated.

Cellule t immunoglobulina e mucina domain&ndash;containing 3 (Tim-3) &egrave; un recettore inibitorio che &egrave; espresso sulle cellule T esaurite durante l&#39;infezione con virus HIV-1 e l&#39;epatite C. Al contrario, Tim-3 espressione e funzione sono difettosi in molteplici malattie autoimmuni umane. Tuttavia, i meccanismi molecolari modulando la funzione Tim-3 non sono ben compresi. Qui vi mostriamo quello antigene leucocitario umano (HLA-B) B-trascrizione associati 3 (Bat3) si lega a e reprime la funzione di, Tim-3. Bat3 protegge T helper tipo 1 (TH1) le cellule da galectin-9&ndash;mediated morte cellulare e promuove la proliferazione sia proinflammatory cytokine produzione. Cellule T Bat3-carenti hanno elevata espressione di molecole associate all&#39;esaurimento come Tim-3, Lag3, Prdm1 e Pbx3, e Bat3 atterramento in cellule T CD4 + mielina-antigen&ndash;specific marcatamente inibisce lo sviluppo di encefalomielite autoimmune sperimentale, promuovendo nel contempo l&#39;espansione di una disfunzionale Tim-3hi, popolazione interferone-&gamma; (IFN-&gamma;) loCD4 + cellulare. Inoltre, espressione di Bat3 &egrave; ridotto in Tim esaurito-3 + T cells da tumori del mouse e gli individui HIV-1&ndash;infected. Questi dati indicano che Bat3 agisce come un inibitore della Tim-3&ndash;dependent esaurimento e cellule morte. Bat3 pu&ograve; cos&igrave; rappresentare un obiettivo terapeutico praticabile in malattie autoimmuni, infezioni croniche e tumori.

Bat3 promuove le risposte delle cellule T e autoimmunit&agrave; reprimendo esaurimento e morte cellulare Tim-3&ndash;mediated.

Regulatory T cells (Tregs) are potent immune modulators, but their precise role in HIV pathogenesis remains incompletely understood. Most studies to date have focused on frequencies or phenotypes of 'bulk' Treg populations. However, although antigen-specific Tregs have been reported in other diseases, HIV-1 epitope-specific Tregs have not been described to date. We here report the first identification of functional HIV-1-Gag-specific regulatory T cells using human leukocyte antigen class II tetramer staining in HIV-1-infected individuals.

Identification of HIV-1-specific regulatory T-cells using HLA class II tetramers.

Les lymphocytes T r&eacute;gulateurs (Tregs) sont des immunomodulateurs puissants, mais leur r&ocirc;le pr&eacute;cis dans la pathog&eacute;n&egrave;se du VIH reste incompl&egrave;tement comprise. La plupart des &eacute;tudes &agrave; ce jour portent sur des fr&eacute;quences ou des ph&eacute;notypes de &laquo; en vrac &raquo; Treg des populations. Cependant, bien que Tregs antig&egrave;ne-sp&eacute;cifiques ont &eacute;t&eacute; signal&eacute;s dans d&#39;autres maladies, Tregs &eacute;pitope sp&eacute;cifique du VIH-1 n&#39;ont pas &eacute;t&eacute; d&eacute;crits &agrave; ce jour. Nous rapportons ici la premi&egrave;re identification de fonctionnelles sp&eacute;cifiques au VIH-1-Gag lymphocytes T r&eacute;gulateurs &agrave; l&#39;aide de human leukocyte antigen classe II t&eacute;tram&egrave;re coloration chez les personnes infect&eacute;es par le VIH-1.

Identification des lymphocytes-T r&eacute;gulateurs sp&eacute;cifiques au VIH-1 &agrave; l&#39;aide de t&eacute;tram&egrave;res HLA classe II.

Cellule T regolatorie (Tregs) sono potenti modulatori immuni, ma loro preciso ruolo nella patogenesi dell&#39;HIV rimane non completamente capito. Maggior parte degli studi fino ad oggi si sono concentrati su frequenze o fenotipi di &#39;massa&#39; Treg popolazioni. Tuttavia, sebbene Tregs antigene-specifici sono stati segnalati in altre malattie, Tregs epitopo specifico dell&#39;HIV-1 non &egrave; stata descritta fino ad oggi. Riportiamo qui la prima identificazione di funzionale dell&#39;HIV-1-Gag-specifiche cellule T regolatorie utilizzando tetramero di umano del leucocita antigen classe II colorazione in individui HIV-1-infected.

Identificazione di HIV-1-specifiche cellule T regolatorie utilizzando tetrameri II classe HLA.

Blockade of costimulation signaling required for immune response, such as CD40/CD40L and CD28/B7, is a reasonable strategy to prevent rejection and in defined combinations may allow donor specific tolerance. Indeed, in rodents, costimulation blockade with CD28/B7 antagonists or with CD40Ig was able to induce regulatory T cells and transplant tolerance whereas in primates, anti-CD40 antibodies, anti-CD40L antibodies or CTLA4Ig, used as monotherapy, significantly delayed graft rejection.

Gene transfer of human CD40Ig does not prevent rejection in a non-human primate kidney allotransplantation model.

Blocus de costimulation signalisation requis pour le syst&egrave;me immunitaire, comme le CD40/CD40L et B7/CD28, est une strat&eacute;gie raisonnable pour pr&eacute;venir le rejet et dans des combinaisons d&eacute;termin&eacute;es peuvent permettre la tol&eacute;rance sp&eacute;cifique de donateurs. En effet, chez les rongeurs, blocus de costimulation CD28/B7 antagonistes ou avec CD40Ig a pu induire les cellules T r&eacute;gulatrices et la tol&eacute;rance de transplantation, tandis que chez les primates, anticorps anti-CD40, anticorps anti-CD40L ou CTLA4Ig, utilis&eacute; en monoth&eacute;rapie, consid&eacute;rablement retard&eacute; le rejet du greffon.

Transfert de g&egrave;nes de CD40Ig humaine n&#39;emp&ecirc;che pas de rejet dans un mod&egrave;le d&#39;allogreffe r&eacute;nale primate non humain.

Blocco di costimulation segnalazione necessaria per la risposta immunitaria, come CD40/CD40L e CD28/B7, &egrave; una strategia ragionevole per prevenire il rigetto e in combinazioni definite possa consentire tolleranza specifico donatore. Infatti, nei roditori, blocco costimulation con CD28/B7 antagonisti o CD40Ig fu in grado di indurre le cellule T regolatorie e tolleranza di trapianto, mentre nei primati, gli anticorpi anti-CD40, anticorpi anti-CD40L o CTLA4Ig, usato come monoterapia, significativamente ritardata innesto rifiuto.

Mathieu Angin

Ragon Institute of MGH, MIT, and Harvard

New Tools to Expand Regulatory T Cells from HIV-1-infected Individuals