Indolamina-2,3-dioxigenase (IDO) e o catabolismo do triptofano estão envolvidos no controle da imunidade inata e adaptativa contra patógenos. Investigamos o papel da IDO na paracoccidiodomicose pulmonar (PCM) de animais suscetíveis (B10.A) e resistentes (A/J) ao fungo. Observou-se uma ação marcante da IDO ao início da doença de camundongos B10.A onde a enzima controla a carga fúngica mas, também, induz anergia de células TCD4+ e TCD8+, creditada em parte à expansão de células Treg e aumento de linfócitos em apoptose. Em camundongos A/J, a IDO controla a carga fúngica inicial, porém, o seu efeito supressor sobre linfócitos TCD4+ é somente observado na 8ª semana. Assim como em camundongos B10.A, a IDO mostrou-se indutora de células Treg e linfócitos em apoptose durante a imunidade desenvolvida por camundongos A/J. Em conclusão, foi demonstrado pela primeira vez que a IDO exerce um importante mecanismo microbicida e imunorregulador na PCM de hospedeiros resistentes e suscetíveis ao P. brasiliensis. / Indoleamine-2, 3-dioxygenase (IDO) and tryptophan catabolism are involved in the control of innate and adaptive immunity against pathogens. We investigated the role of IDO in the pulmonary paracoccidiodomycosis developed by susceptible (B10.A) and resistant (A/J) mice to the fungus. We verified that IDO plays a different effect in innate the immunity of B10.A and A/J mice. Early in the infection, IDO controlled the fungal loads but also induced anergy of CD4+ and CD8+ T cells of B10.A mice. T cell anergy was partially due to the expansion of Treg cells and increased apoptosis of lymphocytes. In resistant mice, IDO controlled the initial fungal loads, but exerted a suppressive effect on T lymphocytes only at week 8. As in B10.A mice IDO was shown to induce Treg cells and apoptosis of lymphocytes in the course of immune response developed by resistant mice. In conclusion our work showed for the first time that IDO play an important role in the fungicidal and immunoregulatory mechanisms developed by susceptible and resistant mice to P. brasiliensis infection.

Os tumores carcinoides típicos broncopulmonares (TCTB) são considerados neoplasias bem diferenciadas e as menos agressivas dentro do espectro dos tumores neuroendócrinos. Entretanto, metástases linfonodais e hematogênicas tem sido encontradas em número considerável de casos e não existem, até o momento, estudos relacionados aos mecanismos de escape imune tumoral em TCTB. Alguns trabalhos tem relacionado a expressão da enzima indoleamine 2,3-dioxigenase (IDO) em células neoplásicas como fator responsável pela aquisição de tolerância tumoral. Além disso, os níveis de infiltração linfocitária intratumoral parecem estar associados com prognóstico e sobrevida nesses tumores. O principal objetivo deste estudo foi determinar os níveis de expressão intratumorais da IDO e sua possível aplicação como marcador biológico de metástases em TCTB. Além disso, também foi estabelecido o padrão de infiltração linfocitária intratumoral e analisada sua provável correlação com os níveis de expressão da IDO. Portanto, realizou-se uma coorte retrospectiva multicêntrica no qual 64 pacientes submetidos à cirurgia de ressecção de TCTB entre 1981 e 2003 foram selecionados. O período de seguimento pós-operatório foi de 5 anos e a ocorrência de metástases linfonodais (hilar ou mediastinal) e hematogênicas foi avaliada através de tomografia computadorizada. Os níveis da expressão da IDO e de infiltração linfocitária intratumoral foram avaliados através de estudo imunohistoquímico. Os resultados obtidos mostraram que dos 64 pacientes selecionados, 17 (26.5%) apresentaram qualquer tipo de metátases durante o estudo: linfonodal, hematogênica ou ambas. A expressão da IDO foi encontrada em níveis diferentes de intensidade em mais de 80% das células dos TBCT. Entretanto, a análise univariada não mostrou nenhuma diferença significante na expressão da IDO entre grupos com e sem metástase (p=0,9 e p=0,3 pela análise semi-quantitativa e quantitativa, respectivamente). A quantificação dos linfócitos em todos os grupos estudados demonstrou predominância de linfócitos T CD8+, quando comparado aos linfócitos T CD4+(p< 0.01). Nenhuma diferença na infiltração intratumoral de linfócitos T CD8+ foi encontrada entre grupos com e sem metástase (p=0,98). Entretanto, a quantificação de linfócitos T CD4+ foi nula nos grupos com qualquer tipo de metástase (p=0,01), e nos casos com metástase linfonodal (p=0,02). Nenhuma correlação entre os níveis da expressão da IDO e da infiltração linfocitária intratumoral foi identificada nos grupos analisados (r= -0.2 e p=0,1 para ambos os grupos). Conclui-se que, a expressão intratumoral da IDO não apresenta correlação com a ocorrência de metástase nos TBCT. Apesar de nenhuma diferença ter sido identificada na infiltração intratumoral de linfócitos T CD8+ nos grupos com e sem metástase, a ausência de infiltração de linfócitos T CD4+ está associado à ocorrência do evento estudado. Estes linfócitos parecem conferir um efeito protetor evitando o escape tumoral / Typical bronchopulmonary carcinoid tumors (TBCT) are considered the less aggressive neoplasm within the spectrum of neuroendocrine tumors. However, regional nodes and haematogenic metastasis occur in a considerable rate and no data regarding immune escape mechanisms in these tumors are available. Some studies have implicated indoleamine 2,3 dioxygenase (IDO) expression in malignant cells as the responsible for tumor tolerance. Also, levels of tumor infiltrating lymphocytes (TILs) seem to be related with prognosis and survival. Our aim in this study was to determine intratumoral IDO expression levels and the value of this variable as a predictive marker of TBCT metastasis. Thus, TILs pattern was determined and correlation with intratumoral IDO expression analyzed. For this purpose, a multicenter retrospective cohort study was performed and 64 patients operated on for TBCT between 1981 and 2003 were enrolled. Follow-up period was 5 years and regional or haematogenic metastasis was assessed by computerized tomography (CT) scan. Levels of IDO expression and TILs were assessed by immunohistochemical study. The results obtained showed that of all 64 patients, 17 (26,5%) presented with any metastasis during the study: regional nodes, haematogenic or both. IDO expression was found in different intensity levels in over 80% of TBCT cells. However, univariate analysis showed no significant difference in IDO expression between groups with and without metastasis (p=0,9 and p=0,3 for semi-quantitative and quantitative analysis respectively). TILs quantification in all studied groups demonstrated predominance of CD8+ TILs when compared to CD4+ TILs (p<0,01). No difference in CD8+ TILs was found between groups with and without metastasis (p=0,98). However CD4+ TILs quantification was null in the groups with any metastasis (p=0,01), and regional nodes metastasis (p=0,02). No correlation between IDO expression levels and TILs was identified in all analyzed groups(r= -0,2 and p=0,1 for both groups). In conclusion, these data shows that intratumoral IDO expression do not correlate with TBCT metastasis. Even though no difference in CD8+ TILs between groups with and without metastasis was found, absence of CD4+ TILs is associated with the studied event. These cells seem to confer a protective effect against tumoral immune escape

Os tumores carcinoides típicos broncopulmonares (TCTB) são considerados neoplasias bem diferenciadas e as menos agressivas dentro do espectro dos tumores neuroendócrinos. Entretanto, metástases linfonodais e hematogênicas tem sido encontradas em número considerável de casos e não existem, até o momento, estudos relacionados aos mecanismos de escape imune tumoral em TCTB. Alguns trabalhos tem relacionado a expressão da enzima indoleamine 2,3-dioxigenase (IDO) em células neoplásicas como fator responsável pela aquisição de tolerância tumoral. Além disso, os níveis de infiltração linfocitária intratumoral parecem estar associados com prognóstico e sobrevida nesses tumores. O principal objetivo deste estudo foi determinar os níveis de expressão intratumorais da IDO e sua possível aplicação como marcador biológico de metástases em TCTB. Além disso, também foi estabelecido o padrão de infiltração linfocitária intratumoral e analisada sua provável correlação com os níveis de expressão da IDO. Portanto, realizou-se uma coorte retrospectiva multicêntrica no qual 64 pacientes submetidos à cirurgia de ressecção de TCTB entre 1981 e 2003 foram selecionados. O período de seguimento pós-operatório foi de 5 anos e a ocorrência de metástases linfonodais (hilar ou mediastinal) e hematogênicas foi avaliada através de tomografia computadorizada. Os níveis da expressão da IDO e de infiltração linfocitária intratumoral foram avaliados através de estudo imunohistoquímico. Os resultados obtidos mostraram que dos 64 pacientes selecionados, 17 (26.5%) apresentaram qualquer tipo de metátases durante o estudo: linfonodal, hematogênica ou ambas. A expressão da IDO foi encontrada em níveis diferentes de intensidade em mais de 80% das células dos TBCT. Entretanto, a análise univariada não mostrou nenhuma diferença significante na expressão da IDO entre grupos com e sem metástase (p=0,9 e p=0,3 pela análise semi-quantitativa e quantitativa, respectivamente). A quantificação dos linfócitos em todos os grupos estudados demonstrou predominância de linfócitos T CD8+, quando comparado aos linfócitos T CD4+(p< 0.01). Nenhuma diferença na infiltração intratumoral de linfócitos T CD8+ foi encontrada entre grupos com e sem metástase (p=0,98). Entretanto, a quantificação de linfócitos T CD4+ foi nula nos grupos com qualquer tipo de metástase (p=0,01), e nos casos com metástase linfonodal (p=0,02). Nenhuma correlação entre os níveis da expressão da IDO e da infiltração linfocitária intratumoral foi identificada nos grupos analisados (r= -0.2 e p=0,1 para ambos os grupos). Conclui-se que, a expressão intratumoral da IDO não apresenta correlação com a ocorrência de metástase nos TBCT. Apesar de nenhuma diferença ter sido identificada na infiltração intratumoral de linfócitos T CD8+ nos grupos com e sem metástase, a ausência de infiltração de linfócitos T CD4+ está associado à ocorrência do evento estudado. Estes linfócitos parecem conferir um efeito protetor evitando o escape tumoral / Typical bronchopulmonary carcinoid tumors (TBCT) are considered the less aggressive neoplasm within the spectrum of neuroendocrine tumors. However, regional nodes and haematogenic metastasis occur in a considerable rate and no data regarding immune escape mechanisms in these tumors are available. Some studies have implicated indoleamine 2,3 dioxygenase (IDO) expression in malignant cells as the responsible for tumor tolerance. Also, levels of tumor infiltrating lymphocytes (TILs) seem to be related with prognosis and survival. Our aim in this study was to determine intratumoral IDO expression levels and the value of this variable as a predictive marker of TBCT metastasis. Thus, TILs pattern was determined and correlation with intratumoral IDO expression analyzed. For this purpose, a multicenter retrospective cohort study was performed and 64 patients operated on for TBCT between 1981 and 2003 were enrolled. Follow-up period was 5 years and regional or haematogenic metastasis was assessed by computerized tomography (CT) scan. Levels of IDO expression and TILs were assessed by immunohistochemical study. The results obtained showed that of all 64 patients, 17 (26,5%) presented with any metastasis during the study: regional nodes, haematogenic or both. IDO expression was found in different intensity levels in over 80% of TBCT cells. However, univariate analysis showed no significant difference in IDO expression between groups with and without metastasis (p=0,9 and p=0,3 for semi-quantitative and quantitative analysis respectively). TILs quantification in all studied groups demonstrated predominance of CD8+ TILs when compared to CD4+ TILs (p<0,01). No difference in CD8+ TILs was found between groups with and without metastasis (p=0,98). However CD4+ TILs quantification was null in the groups with any metastasis (p=0,01), and regional nodes metastasis (p=0,02). No correlation between IDO expression levels and TILs was identified in all analyzed groups(r= -0,2 and p=0,1 for both groups). In conclusion, these data shows that intratumoral IDO expression do not correlate with TBCT metastasis. Even though no difference in CD8+ TILs between groups with and without metastasis was found, absence of CD4+ TILs is associated with the studied event. These cells seem to confer a protective effect against tumoral immune escape

La réponse immune représente une réponse complexe à laquelle correspond une succession d’événements orchestrés finement. Parmi les mécanismes qui régulent la réponse immune, les lymphocytes T régulateurs (Tregs) assurent le maintien de la tolérance en périphérie et le contrôle des réponses immunes adaptatives. Ils représentent une population hétérogène et leurs mécanismes de suppression sont toujours l’objet d’intenses recherches. Suivant le contexte de suppression et leur nature, les lymphocytes Tregs réalisent une inhibition de l’activation des lymphocytes Th, soit directement, soit via la modulation de la fonction des cellules dendritiques (DC). Dans un modèle d’immunisation par des cellules dendritiques chargées de KLH, les lymphocytes Tregs naturels contrôlent sélectivement l’initiation des réponses de type Th1/CTL spécifiques de l’antigène. Le but de ce travail était de définir quels sont les acteurs potentiels du contrôle de cette réponse. A l’aide de l’anticorps PC61 dirigé contre le récepteur CD25 et éliminant les lymphocytes Tregs naturels, nous avons montré que le ligand de costimulation CD70 joue un rôle clé dans leur régulation de la réponse Th1/CTL (Article 1). Ainsi, dans des conditions normales, la cytokine IL-12 induit principalement l’initiation de la réponse Th1 in vivo, tandis qu’en l’absence de lymphocytes Tregs naturels, la voie CD70/CD27 est une voie alternative d’induction de l’IFN-γ. Cette voie d’activation pourrait être opérationnelle dans certains contextes infectieux lorsque les lymphocytes Tregs sont déstabilisés voire éliminés, par exemple lors d’infections par Toxoplasma gondii ou par les virus HTLV1, SIV ou HIV. Nous avons montré que les lymphocytes Tregs naturels diminuent l’expression du ligand CD70 sur les DC, de manière dépendante de son récepteur CD27. Ensuite, nous nous sommes intéressés à une deuxième population de lymphocytes T régulateurs, les lymphocytes Tregs ICOShigh induits in vivo par le traitement avec l’anticorps anti-CTLA-4. Dans le cadre d’une colite induite par l’agent alkylant TNBS et mettant en jeu une réponse Th1, cette population de lymphocytes Tregs amplifiée par le traitement à l’anticorps anti-CTLA-4 régule la réponse immune via la cytokine anti-inflammatoire IL-10 et l’enzyme immunosuppressive IDO (Article 2). Ainsi, les résultats obtenus nous ont permis de répondre à notre objectif et de définir certains mécanismes de suppression des lymphocytes Tregs naturels et des lymphocytes Tregs induits. Dans la dernière partie de ce travail, nous avons cherché à comparer les populations de lymphocytes Tregs naturels et ICOShigh présentes dans l’intestin d’une souris naïve. Une analyse transcriptomique a révélé que ces deux populations s’opposent sur les plans phénotypique et fonctionnel. Nous proposons un modèle dans lequel les deux populations de lymphocytes Tregs agiraient en synergie pour maintenir l’homéostasie intestinale. Les lymphocytes Tregs ICOShigh différenciés au niveau local et continuellement activés contrôleraient la réponse inflammatoire associée à la présence de la flore commensale. Les lymphocytes Tregs naturels, en quiescence dans les ganglions mésentériques, n’interviendraient qu’en cas d’infection par des pathogènes. L’étude des lymphocytes T régulateurs soulève un certain nombre de concepts clés de l’immunité : la spécificité des réponses, la distinction des microorganismes commensaux et pathogènes… Mieux connaître les lymphocytes Tregs dans un modèle murin permettra de mieux comprendre les réponses inflammatoires intestinales chroniques observées chez l'homme et d’envisager, à terme, de nouveaux traitements. / An immune response is complex and implies numerous sequential events. It is regulated by different mechanisms, among which regulatory T cells maintain peripheral tolerance and control adaptive immune responses. Regulatory T cells are very heterogeneous and suppress immune responses through different mechanisms, still under investigation. They can inhibit T cell activation directly or through the modulation of dendritic cell function, depending on their nature and the tissular context. In a dendritic cell-mediated immunization model, naturally occurring regulatory T cells selectively control the priming of antigen-specific Th1/CTL responses. Our goal was to define the potential actors of this control, targeted by natural regulatory T cells. Using the PC61 antibody which targets and depletes these cells, we showed that the costimulation ligand CD70 plays a key role in their control of Th1/CTL responses (first article). We showed that mainly IL-12 provokes Th1 development in normal conditions, wheras CD70 plays a major role in priming Th1 responses in the absence of natural Tregs. This pathway can be operational if regulatory T cells are destabilized or even depleted, for example during infection with Toxoplasma gondii or with HTLV1, SIV or HIV. We showed that natural Tregs downregulate CD70 expression on the surface of DCs. Next, we focused on another regulatory T cell population, induced in vivo by the anti-CTLA-4 mAb treatment. In a model of pro-Th1 colitis, induced by the alkylating agent TNBS, these ICOShigh regulatory T cells exert an IL-10 and IDO-dependant control over the immune response (second article). Thus, we succeeded in determining some control mechanisms of the immune response targeted by two populations of regulatory T cells. Finally, we compared two regulatory T cell populations: naturally occurring regulatory T cells and ICOShigh regulatory T cells from the intestines of naïve mice. A transcriptional analysis revealed two populations phenotypically and functionally distinct. We proposed a model in which these populations act synergistically and both maintain intestinal homeostasis. ICOShigh regulatory T cells might control commensal gut flora-specific inflammatory responses and quiescent natural regulatory T cells from mesenteric lymph nodes might control potential pathogen infections. As a conclusion, this study raises some immunological issues: specificity of immune responses, distinction between commensal and pathogenic microorganisms… A better knowledge of these regulatory populations will lead to a better understanding of human intestinal responses and in the medium term will lead to new therapeutic approaches and tools.

TDO utilizes b-type heme as a cofactor to activate dioxygen and insert two oxygen atoms into free L-tryptophan. We revealed two unidentified enzymatic activities of ferric TDO from Ralstonia metallidurans, which are peroxide driven oxygenation and catalase-like activity. The stoichiometric titration suggests that two moles of H2O2 were required for the production of one mole of N-formylkynurenine. We have also observed monooxygenated-L-tryptophan. Three enzyme-based intermediates were sequentially detected in the peroxide oxidation of ferric TDO in the absence of L-Trp including compound I-type and compound ES-type Fe-oxo species. The Fe(IV) intermediates had an unusually large quadrupole splitting parameter of 1.76(2) mm/s at pH 7.4. Density functional theory calculations suggest that it results from the hydrogen bonding to the oxo group. We have also demonstrated that the oxidized TDO was activated via a homolytic cleavage of the O-O bond of ferric hydroperoxide intermediate via a substrate dependent process to generate a ferrous TDO. We proposed a peroxide activation mechanism of the oxidized TDO. The TDO has a relatively high redox potential, the protonated state of the proximal histidine upon substrate binding as well as a common feature of the formation of ferric hydroxide species upon substrate or substrate analogues binding. Putting these together, we have proposed a substrate-based activation mechanism of the oxidized TDO. Our work also probed the role of histidine 72 as an acid-base catalyst in the active site. In H72S and H72N mutants, one water molecule plays a similar role as that of His72 in wild type TDO. MauG is a c-type di-heme enzyme which catalyze the biosynthesis of the protein-derived cofactor tryptophan tryptophylquinone. Its natural substrate is a monohydroxylated tryptophan residue present in a 119-kDa precursor protein of methylamine dehydrogenase (MADH). We have trapped a novel bis-Fe(IV) intermediate from MauG, which is remarkably stable. A tryptophanyl radical intermediate of MADH has been trapped after the reaction of the substrate with the bis-Fe(IV) intermediate. Analysis by high-resolution size-exclusion chromatography shows that MauG can tightly bind to the biosynthetic precursor and form a stable complex, but the mature protein substrate does not.

La réponse immune représente une réponse complexe à laquelle correspond une succession d’événements orchestrés finement. Parmi les mécanismes qui régulent la réponse immune, les lymphocytes T régulateurs (Tregs) assurent le maintien de la tolérance en périphérie et le contrôle des réponses immunes adaptatives. Ils représentent une population hétérogène et leurs mécanismes de suppression sont toujours l’objet d’intenses recherches. Suivant le contexte de suppression et leur nature, les lymphocytes Tregs réalisent une inhibition de l’activation des lymphocytes Th, soit directement, soit via la modulation de la fonction des cellules dendritiques (DC). <p>Dans un modèle d’immunisation par des cellules dendritiques chargées de KLH, les lymphocytes Tregs naturels contrôlent sélectivement l’initiation des réponses de type Th1/CTL spécifiques de l’antigène. Le but de ce travail était de définir quels sont les acteurs potentiels du contrôle de cette réponse. A l’aide de l’anticorps PC61 dirigé contre le récepteur CD25 et éliminant les lymphocytes Tregs naturels, nous avons montré que le ligand de costimulation CD70 joue un rôle clé dans leur régulation de la réponse Th1/CTL (Article 1). Ainsi, dans des conditions normales, la cytokine IL-12 induit principalement l’initiation de la réponse Th1 in vivo, tandis qu’en l’absence de lymphocytes Tregs naturels, la voie CD70/CD27 est une voie alternative d’induction de l’IFN-γ. Cette voie d’activation pourrait être opérationnelle dans certains contextes infectieux lorsque les lymphocytes Tregs sont déstabilisés voire éliminés, par exemple lors d’infections par Toxoplasma gondii ou par les virus HTLV1, SIV ou HIV. Nous avons montré que les lymphocytes Tregs naturels diminuent l’expression du ligand CD70 sur les DC, de manière dépendante de son récepteur CD27. <p>Ensuite, nous nous sommes intéressés à une deuxième population de lymphocytes T régulateurs, les lymphocytes Tregs ICOShigh induits in vivo par le traitement avec l’anticorps anti-CTLA-4. Dans le cadre d’une colite induite par l’agent alkylant TNBS et mettant en jeu une réponse Th1, cette population de lymphocytes Tregs amplifiée par le traitement à l’anticorps anti-CTLA-4 régule la réponse immune via la cytokine anti-inflammatoire IL-10 et l’enzyme immunosuppressive IDO (Article 2). Ainsi, les résultats obtenus nous ont permis de répondre à notre objectif et de définir certains mécanismes de suppression des lymphocytes Tregs naturels et des lymphocytes Tregs induits. <p>Dans la dernière partie de ce travail, nous avons cherché à comparer les populations de lymphocytes Tregs naturels et ICOShigh présentes dans l’intestin d’une souris naïve. Une analyse transcriptomique a révélé que ces deux populations s’opposent sur les plans phénotypique et fonctionnel. Nous proposons un modèle dans lequel les deux populations de lymphocytes Tregs agiraient en synergie pour maintenir l’homéostasie intestinale. Les lymphocytes Tregs ICOShigh différenciés au niveau local et continuellement activés contrôleraient la réponse inflammatoire associée à la présence de la flore commensale. Les lymphocytes Tregs naturels, en quiescence dans les ganglions mésentériques, n’interviendraient qu’en cas d’infection par des pathogènes.<p>L’étude des lymphocytes T régulateurs soulève un certain nombre de concepts clés de l’immunité :la spécificité des réponses, la distinction des microorganismes commensaux et pathogènes… Mieux connaître les lymphocytes Tregs dans un modèle murin permettra de mieux comprendre les réponses inflammatoires intestinales chroniques observées chez l'homme et d’envisager, à terme, de nouveaux traitements.<p>/<p>An immune response is complex and implies numerous sequential events. It is regulated by different mechanisms, among which regulatory T cells maintain peripheral tolerance and control adaptive immune responses. Regulatory T cells are very heterogeneous and suppress immune responses through different mechanisms, still under investigation. They can inhibit T cell activation directly or through the modulation of dendritic cell function, depending on their nature and the tissular context.<p>In a dendritic cell-mediated immunization model, naturally occurring regulatory T cells selectively control the priming of antigen-specific Th1/CTL responses. Our goal was to define the potential actors of this control, targeted by natural regulatory T cells. Using the PC61 antibody which targets and depletes these cells, we showed that the costimulation ligand CD70 plays a key role in their control of Th1/CTL responses (first article). We showed that mainly IL-12 provokes Th1 development in normal conditions, wheras CD70 plays a major role in priming Th1 responses in the absence of natural Tregs. This pathway can be operational if regulatory T cells are destabilized or even depleted, for example during infection with Toxoplasma gondii or with HTLV1, SIV or HIV. We showed that natural Tregs downregulate CD70 expression on the surface of DCs.<p>Next, we focused on another regulatory T cell population, induced in vivo by the anti-CTLA-4 mAb treatment. In a model of pro-Th1 colitis, induced by the alkylating agent TNBS, these ICOShigh regulatory T cells exert an IL-10 and IDO-dependant control over the immune response (second article). Thus, we succeeded in determining some control mechanisms of the immune response targeted by two populations of regulatory T cells.<p>Finally, we compared two regulatory T cell populations: naturally occurring regulatory T cells and ICOShigh regulatory T cells from the intestines of naïve mice. A transcriptional analysis revealed two populations phenotypically and functionally distinct. We proposed a model in which these populations act synergistically and both maintain intestinal homeostasis. ICOShigh regulatory T cells might control commensal gut flora-specific inflammatory responses and quiescent natural regulatory T cells from mesenteric lymph nodes might control potential pathogen infections.<p>As a conclusion, this study raises some immunological issues: specificity of immune responses, distinction between commensal and pathogenic microorganisms… A better knowledge of these regulatory populations will lead to a better understanding of human intestinal responses and in the medium term will lead to new therapeutic approaches and tools.<p> / Doctorat en Sciences / info:eu-repo/semantics/nonPublished