Helminth parasites excel at subverting the host’s immune regulatory pathways resulting in immunosuppressed hosts harbouring chronic infections. This immune suppression forms a major barrier to the acquisition of protective Th2 immunity, both in regard to natural infections and potential vaccinations. At the same time, immune downregulation plays a beneficial role in protecting the host from pathology during chronic infection, and epidemiological links between helminth infections and the amelioration of allergy and autoimmunity diseases indicate that helminth-induced immune suppression can be therapeutically applied to the treatment of these conditions. Foxp3+ regulatory T cells (Treg) play central downregulatory roles in controlling reactivity to self-antigens and preventing autoimmune diseases, as well as in limiting inflammatory responses during infection. Helminths induce dominant Foxp3+ Treg responses that play key roles in inhibiting protective immunity and alleviating immunopathology, and that can protect against allergic inflammation. Thus, Foxp3+ Tregs are a fundamental mechanism of immune regulation during helminth infections, and an understanding of the mechanisms governing the induction of Foxp3+ Treg responses is of principal importance for the design of both prophylactic helminth treatments and therapies for allergies and autoimmunity. However, the nature of the T cell co-stimulatory signals driving Treg generation during helminth infection is largely unclear. Recent evidence suggests that the inducible costimulator (ICOS) contributes to Treg control of autoimmune inflammation. Further, ICOS expression is upregulated by Foxp3+ Treg during infection with the filarial nematode Litomosoides sigmodontis suggesting ICOS is important for Treg during helminth infection. Therefore, we investigated the role of ICOS in helminth-induced Treg responses. Similar to L. sigmodontis infection, Foxp3+ Treg increased ICOS expression in response to infection with the intestinal nematode Heligmosomoides polygyrus and with the blood trematode Schistosoma mansoni. Functionally, ICOS was required for the optimal expansion of lymphoid Treg numbers during early stage H. polygyrus infection and following the onset of the acute egg phase of S. mansoni infection suggesting common pathways for Treg induction by diverse helminth species. Whilst helminth induced proliferation and activation of Foxp3+ Treg was ICOS independent, ICOS was essential for Treg survival in settings of homeostasis and helminth infection. In contrast to the lymph node, Treg responses in the intestinal lamina propria (LP) of ICOS-/- mice were increased due to expanded natural Treg. Following H. polygyrus infection Foxp3+ Helios- CD4+ T cells preferentially expanded in wild-type (WT) mice but not in ICOS deficient mice suggesting ICOS is required for the expansion of adaptive Treg at the site of intestinal nematode infection. Functionally, ICOS supports Treg, but not effector T cells (Teff), H. polygyrus induced IL- 10 production suggesting ICOS differentially regulates Treg and Teff. At the H. polygyrus infection site, ICOS acted to downregulate CD4+ T cell Th2 cytokine production. Conversely, in the reactive lymph node ICOS signalling promoted Th2 immune responses, possibly by maintaining the pool of IL-4 secreting type 2 follicular helper T cells. Thus, ICOS has different effects on Th2 immunity depending on tissue location. Because Th2 immunity governs expulsion of H. polygyrus parasites, the differences in Th2 responses between lymph node and infection site could explain why ICOS deficiency did not impact worm burden. Protective immunity to long-lived helminth infection can be quenched in the initial days of infection by the action of Treg. Whether Treg expand and suppress protective immunity during S. mansoni larvae lung transit has not been investigated. We found that in contrast to H. polygyrus and L. sigmodontis infection, early S. mansoni infection did not induce a Treg response suggesting other mechanisms are employed for immune subversion. During the acute egg-phase of S. mansoni infection, Foxp3+ Treg protect the host from damaging egg-induced hepatic immunopathology. Despite reduced Foxp3+ Treg responses, ICOS deficiency did not impact egg-induced immunopathology. Thus, ICOS co-stimulation contributes to early expansion and the continued maintenance of Treg during helminth infection, both in the local lymph node and at the infection site. ICOS is required for Treg function during helminth infection by promoting IL-10 production, whilst its contribution to Th2 effector immunity is tissue specific. In addition, ICOS is dispensable for protective immunity and pathology during helminth infection. As ICOS controls both positive and negative immune responses and can have opposing roles depending on tissue location, an understanding of the consequences of these contradictory effects will be important when considering targeting ICOS therapeutically.

No description available.

European regulation of virtual currencies, its shortcomings and future development Abstract This thesis is focused on the European regulation of virtual currencies, meaning the current Union legal regulation of this phenomenon including further European Union institutions' activities in the area. The aim of the thesis is to introduce the existing approach towards virtual currencies as well as to find some of the shortcomings and to outline the future development of European regulation of virtual currencies. As a part of this thesis, relevant activities associated with distributed ledger technology as a technology related to virtual currencies will be introduced. To achieve the mentioned, the thesis analyzes mainly legislative and non-legislative sources issued by competent institutions of the European Union, equally important are the jurisprudential texts from the area of virtual currencies and related fields. The thesis is divided into five chapters which are further divided into topical subchapters. Each of the chapters includes partial identification of shortcomings and presents the future development in the area. The introductory chapter addresses the introduction of virtual currencies as such and in the context of financial law. Further, technological bases of virtual currencies are described, namely...

BACKGROUND Inducible costimulator (ICOS) and its ligand (ICOSL) are a pair of costimulatory molecules that co-localize in germinal centers (GC). This interaction is critical for the maturation of GC B cells to affinity-matured memory B cells and long-lived plasma cells. Both ICOS and ICOSL are implicated in systemic lupus erythematosus (SLE). It is known that ICOSL sheds from the cell membrane and that the soluble form of ICOSL (sICOSL) is elevated in SLE; though the function of sICOSL is poorly understood. While it is known that binding of ICOSL on antigen-presenting cells (APC) to ICOS on T cells leads to cell signaling resulting in T cell activation and differentiation, there is also some preliminary evidence that reverse signaling may also occur through ICOSL in APCs. The binding interaction between ICOS and sICOSL has not been fully characterized and is important to understand if either molecule is to be targeted therapeutically. The hypothesis evaluated in this study was that the ICOS: ICOSL interaction is a potent and critical mediator of proinflammatory signaling and immune activation that functions both via activated T cell-mediated forward signaling and APC-mediated reverse signaling mechanisms and that ectodomain shedding of ICOSL is a protective mechanism that leads to down-regulation of the proinflammatorysignaling cascade initiated by this interaction. The aim of this thesis is to characterize the binding interaction between ICOS and ICOSL and to provide a review of the literature and discuss future work that would enhance the biological understanding of this interaction and its role in lupus and other autoimmune diseases. METHODS The binding interaction between ICOS and ICOSL was characterized using both soluble proteins and cells with expressed recombinant proteins. Purified soluble ICOSL (sICOSL) was characterized using size-exclusion chromatography multiangle light scattering (SEC-MALS). Surface plasmon resonance (SPR) was used to measure the binding affinity between sICOSL and human ICOS fused to the fragment crystallizable (Fc) portion of an immunoglobulin molecule (hICOS.Fc). The binding interaction was further characterized to account for avidity between hICOS.Fc and sICOSL and between hICOS.Fc and ICOSL expressed recombinant on the cell surface using a solution-based binding method. RESULTS Expressed recombinant and purified sICOSL dimerized over time and with increasing temperatures. The sICOSL: hICOS.Fc interaction did not follow a typical 1:1 binding interaction. In-solution binding experiments resulted in a tighter equilibrium dissociation binding constant (KD) than the surface-based results obtained by SPR. The KD for hICOS.Fc binding to human ICOSL(hICOSL) expressed on cells agreed well with the KD for hICOS.Fc to the soluble protein, indicating that the in-solution binding measurement may measure binding avidity rather than affinity and that this may be the more physiologically relevant interaction. CONCLUSIONS I show in the experimental part of this study that the interaction between ICOS and ICOSL is quite potent and that much of the binding strength is due to avidity, or the combined strength of multiple parts of the molecules interacting with one another, rather than the affinity alone. As this interaction is implicated in SLE pathogenesis, it would be useful to develop a clearer understanding of the most relevant physiological form of these molecules (soluble or transmembrane) and of the biological signaling events that are initiated via this interaction in order to determine whether targeting ICOS or ICOSL may be therapeutically viable approaches.

Au cours de ces 20 dernières années, les inhibiteurs de "checkpoint blockade" sont une des stratégies les plus prometteuses pour l’immunothérapie du cancer. une partie de l'effet anti-tumoral de ces inhibiteurs reposerait sur la déplétion des lymphocytes T régulateurs (TREG). ici, nous avons examine si la forte expression d'ICOS sur ces cellules pourrait être utilisée comme marqueur pour cibler les TREG et améliorer le rejet tumoral. nous rapportons qu'un nouvel acm anti-ICOS humain deplete préférentiellement les TREG dans un modèle de souris nsg humanisées (cd34+) menant a une augmentation du rapport cd8+/treg. toutefois, cela ne suffisait pas a influer sur la croissance de la lignée de cancer du sein mda-mb-231. nous avons administre du cyclophosphamide (CTX) a faible dose pour induire de la mort cellulaire immunogène et stimuler la réponse anti-tumorale. le traitement des animaux avec une combinaison CTX + anti-ICOS conduit 0 une réduction drastique de la croissance tumorale alors que les traitements individuels ont des effets modérés. Grâce a la cytométrie de masse (cytof), nous avons observe une plus forte expression de cd45ro, hla-dr et ki-67 sur les ltcd8+ du groupe traite par la combinaison. de plus, d'autres analyses suggèrent que les monocytes et PDC humains et les cellules myéloïdes murines pourraient être impliqués dans cet effet. au final, nos résultats sont la première démonstration que les souris humanisées peuvent être utilisées pour développer de nouvelles immunothérapies anti-cancer et indiquent que le ciblage TREG avec une combinaison d'ACM anti-ICOS et la chimiothérapie est une strat2gie pertinente pour renforcer la réponse anti-tumorale. / Checkpoint blockade inhibitors are the most promising and effective strategy for t-cell mediated cancer immunotherapy of the past 20 years. Part of the anti-tumoral effect of these checkpoint inhibitors might be due to regulatory T cell (treg) depletion. Here, we investigated whether the reported high expression of icos on treg might be used as a flag to target treg and improve tumor rejection. We report that a novel anti-human icos mab preferentially depleted treg in immunodeficient nsg mice reconstituted with cd34+ progenitors, leading to an increased cd8+/treg ratio. However, this was insufficent to affect growth of the breast cancer cell line mda-mb-231. We thus administered low dose cyclophosphamide (ctx) to induce immunogenic cell death and stimulate anti-tumor response. Treatment of humanized mice with a combination of ctx+ anti-icos mab led to a drastic reduction in tumor growth whereas single treatments had only moderated effect. Using mass cytometry (cytof), we observed higher expression of cd45ro, hla-dr and ki67 on tcd8+ of the combined-treatment group. Accordingly, depletion of cd8+ t cells partly abolished the therapeutic effect of the combination. Moreover, additional analyses suggest that human monocytes and pdc and murine myeloid cells are involved in this effect. Altogether, our results represent the first demonstration that humanized mice can be used to develop novel therapeutic strategies for cancer immunotherapy and indicate that targeting treg with a combination of anti-icos mab and chemotherapy is a relevant strategy to release the immune response to the tumor.

La spondyloarthrite (SpA) est un rhumatisme inflammatoire chronique fréquent avec une prévalence de 0,43% en France, fortement associée à HLA-B27. À l’heure actuelle, il n’existe aucun traitement curatif et les mécanismes physiopathologiques impliqués restent méconnus. Afin de mieux comprendre les mécanismes immunologiques impliqués dans le développement de la SpA, nous avons étudié deux populations cellulaires clé, les cellules dendritiques (DC) et les lymphocytes T (LT) CD4+, chez le rat transgénique pour le HLA-B27 et la β2 microglobuline humaine (rat B27) qui développe spontanément tous les symptômes de la SpA. Il a été démontré que l’accumulation de lymphocytes T helper producteurs d’interleukine 17 (IL-17) pathogénique (lymphocyte Th17), et plusieurs défauts fonctionnels des cellules dendritiques (DCs) sont corrélés avec le développement de la SpA chez les rats B27.Nous nous sommes tout d’abord intéressés aux lymphocytes T régulateurs (Treg), dont le rôle est d’empêcher l’établissement d’une réponse immune pathogène pour l’hôte, chez le rat B27. Nous avons découvert que les Treg de rats B27 présentent un phénotype pro-inflammatoire (surexpression d’IL-17 et sous-expression d’IL-10 anti-inflammatoire), lié à la surexpression de la molécule ICOS. De plus, la sévérité des signes cliniques chez les rats B27 n’exprimant pas ICOS (rats B27 ICOS KO) est diminuée comparé aux animaux HLA-B27 sauvages. Cette protection partielle est corrélée à une réduction de la proportion de lymphocytes Th17. Ces résultats mettent en lumière le rôle majeur d’ICOS dans la physiopathologie de la SpA du rat.La deuxième partie de ce travail s’est concentrée sur les conséquences de la sous-expression d’IL-27 par les DC de rats B27, cytokine connue pour inhiber le développement des Th17. Nous avons observé que l’addition d’IL-27 exogène permet de diminuer la production d’IL-17 et d’augmenter la synthèse d’IL-10 anti-inflammatoire par les LT différenciés (T effecteurs et Treg) et les LT naïfs de rats B27 différenciés in vitro. De façon intéressante, l’IL-27 réduit également la synthèse d’IL-17 par les LT CD4+ circulants de patients atteints de SpA.Ces travaux démontrent pour la première fois le rôle clé de l’IL-27 et d’ICOS dans le contrôle de l’inflammation chez le rat B27 et suggèrent fortement que ces deux molécules sont de nouvelles cibles thérapeutiques prometteuses dans la SpA. / Spondyloarthritis (SpA) is a frequent chronic rheumatic inflammatory disorder with a prevalence of 0.43% in France and closely associated to HLA-B27. To date, there is no curative treatment and pathophysiological mechanisms involved in this pathology remain elusive. To better understand these mechanisms, we studied two crucial cell populations, dendritic cells (DC) and CD4+ T cells in rats transgenic for HLA-B27 and human β2 microglobulin (B27 rats) which spontaneously develop a phenotype closely resembling human spndyloarthritis. Previous studies demonstrated that accumulation of pathogenic IL-17 producing T cells (Th17 cells) and several function defects of DCs are correlated with SpA development in B27 rats.First, we focused on regulatory T cells, whose role is to prevent the establishment of pathogenic immune responses. We discovered that Treg from B27 rats have a pro-inflammatory phenotype. They overexpress IL-17 and underexpress anti-inflammatory IL-10, linked to ICOS overexpression. Furthermore, B27 rats knock-out for ICOS (B27 ICOS KO rats) have reduced severity of clinical symptoms compared to B27 ICOS WT rats. This protective effect is correlated with a reduced proportion of Th17 cells. These results highlight the crucial role of ICOS in rat SpA physiopathology.In the second part of this work we studied the consequences of IL-27 underexpression by B27 DC, a cytokine known to inhibit Th17 development. Addition of exogenous IL-27 reduces IL-17 and increases IL-10 productions by differentiated T cells (Teff and Treg) and by naive T cells polarized in vitro. Interestingly, IL-27 also reduces IL-17 production by circulating CD4+ T cells isolated from blood of SpA patients.This work demonstrate for the first time the key role of IL-27 and ICOS in the control of inflammation in B27 rats and highly suggest that these molecules may be new promising therapeutic targets in SpA.

The proper regulation of inducible costimulator (ICOS) and its ligand (ICOSL) have been shown to be essential for maintaining immune homeostasis. Loss of either protein results in defective humoral immunity, and overexpression of ICOS results in aberrant antibody production resembling lupus. How ICOSL is regulated in response to ICOS interaction is still unclear. We demonstrate that ADAM10 is the primary physiological sheddase of ICOSL in both mouse and human. Using an in vivo system in which ADAM10 is deleted only on B cells (ADAM10B-/-), elevated levels of ICOSL were seen. This increase is also seen when ADAM10 is deleted from human B cell lines. Identification of the primary sheddase has allowed the characterization of a novel mechanism of ICOS regulation. In wildtype (WT) mice, interaction of ICOSL/ICOS results in ADAM10 induced shedding of ICOSL on B cells and moderate ICOS internalization on T cells. When this shedding is blocked, excessive ICOS internalization occurs. This results in severe defects in T follicular helper (TFH) development and Th2 polarization, seen in a house dust mite exposure model. In addition, enhanced Th1 and Th1 immune responses are seen in experimental allergic encephalomyelitis. Blockade of ICOSL rescues T cell ICOS surface expression and at least partially rescues both TFH numbers and the abnormal antibody production previously reported in these mice. Overall, we propose a novel regulation of the ICOS:ICOSL axis, with ADAM10 playing a direct role in regulating ICOSL as well as indirectly regulating ICOS, thus controlling ICOS:ICOSL-dependent responses. Additionally, we report a specific role for the metalloprotease ADAM10 on B cells in regulating both ICOSL and ICOS in a mouse model of increased humoral immunity using mir146a-/- mice and a model of lymphoproliferative disease using the well characterized lpr model. B6lpr mice lacking ADAM10 on B cells (A10Blpr) have decreased nodal proliferation and T cell accumulation compared to control B6lpr mice. Additionally, A10Blpr mice have a drastic reduction in autoimmune anti-dsDNA antibody production. In line with this, we found a significant reduction in follicular helper T cells (TFH) and germinal center (GC) B cells in these mice. We also show that lymphoproliferation in this model is closely tied to elevated ICOS levels and decreased ICOSL levels. Overall, our data not only shows a role of B cell ADAM10 in controlling autoimmunity, but also increases our understanding of the regulation of ICOS and ICOSL in the context of autoimmunity. Additionally, we found that ADAM17 is important for marginal zone (MZ) B cell development as well as responses to T-independent type 2 (TI2) immunizations. Mice which lack ADAM17 on B cells (A17B) have decreased MZ B cell numbers but have increased levels of antigen specific antibodies in response to TI2 Immunizations. ADAM17 also regulates the level of several surface molecules on plasma cells and MZ B cells necessary for their function and survival. We also show a role for ADAM17 in ILC2 responsiveness to IL-33. In vivo, mice that lack ADAM17 specifically on ILC2s (ADAM17ILC2-/-) exhibit decreased ILC2 expansion in response to intranasal IL-33 as well as Nippostrongylus brasiliensis (Nb) infection. However, ADAM17ILC2-/- mice have normal ILC2 numbers in a naïve state, suggesting this defect in ILC2 function is limited to cell activation. In vitro, ADAM17 inhibited ILC2s have an increased level of apoptosis and less IL-13 production in response to IL-33 compared to vehicle treated ILC2s. The defect in cytokine production following ADAM17 inhibition is not observed in response to IL-25 stimulation, suggesting this defect is limited to IL-33 stimulation Mechanistically, ADAM17 inhibition in ILC2s specifically causes a defect in IL-33 mediated ERK activation, potentially explaining the defective survival and IL-13 production following ADAM17 inhibition in these cells. Additionally, ADAM17 regulates the level of surface IL1R2 which may affect IL-33 signaling in ILC2s.

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Comunicação e Expressão, Programa de Pós-Graduação em Literatura, Florianópolis, 2016. / Made available in DSpace on 2016-05-24T17:58:25Z (GMT). No. of bitstreams: 1 339028.pdf: 1117164 bytes, checksum: ca9b210234c4ac0807bbffc5a97467de (MD5) Previous issue date: 2016 / Esta tese versa sobre a presença do Estoicismo na obra de José Saramago e os livros analisados são Todos os nomes (1997), Ensaio sobre a cegueira (1995) e O Ano da morte de Ricardo Reis (1984). O Estoicismo estabeleceu diretrizes para que o ser humano consiga chegar à felicidade. No entanto, existem múltiplas possibilidades interpretativas dessas orientações e a principal é a decorrência para a exortação à ação, notabilizada pela personagem da mulher do médico, ou para a apologia à inação, representada pelo protagonista Ricardo Reis. Neste trabalho trazemos a lume a ênfase ética e essas polaridades hermenêuticas, denominadas como estratos estoicos, que estão presentes nas narrativas. A partir dos tópicos, a primazia da razão, o destino e a indiferença, evidenciamos as confluências e as divergências do prêmio Nobel de Literatura em relação aos preceitos estoicos.<br> / Abstract : This thesis deals with the presence of Stoicism in the work of José Saramago and the analyzed books are Todos os nomes (1997) Ensaio sobre a cegueira (1995) and O Ano da morte de Ricardo Reis (1984). Stoicism has established guidelines for the human being achieve happiness. However, there are multiple possible interpretations of these guidelines, and the main one is the result for the call to action, emphasized by the character of the doctor's wife, or the apology for inaction, represented by the protagonist Ricardo Reis. In this work we bring to light the emphasis on ethics and these hermeneutical polarities, called as Stoics strata, which are present in the narratives. From the topics, the primacy of reason, fate and indifference, we noted the confluences and divergences of the Nobel Prize for literature in relation to the Stoics precepts.

Implication de ROQUIN dans la physiopathologie du lymphome T angio-immunoblastique. Le T-LAI est un lymphome T périphérique qui de part sa rareté bénéficie de peu d'études contrairement aux lymphomes B. En France, le T-LAI est le PTCL le plus fréquemment rencontré. Malgré une évolution clinique variable, le T-LAI reste une tumeur agressive dont la survie globale est inférieure à 3 ans. Un des objectifs de notre équipe est donc de mieux comprendre la physiopathologie de ce lymphome et d'identifier des évènements oncogéniques conduisant à son développement. Dans le cadre de ce projet, notre étude s'est portée sur le gène ROQUIN qui code une E3 ubiquitine ligase de la famille RING et dont la mutation est associée à l'apparition d'un syndrome proche du T-LAI chez la souris sanroque.Bien que nous n'ayons détecté aucune mutation dans la séquence codante de ROQUIN nous avons identifié un nouveau transcrit alternatif appelé ROQUIN ØE17. Celui-ci code une protéine qui, comme la forme sauvage, se localise dans les granules de stress et les corps P et interagit avec certains ARNm et micro-ARN. Néanmoins il est le seul à inhiber l'expression de la molécule de costimulation ICOS. ROQUIN ØE17, qui est présent en concentrations variables dans les différentes populations lymphocytaires T n'est quasiment pas exprimé dans les T-LAI. De ce fait, la perte du transcrit ROQUIN ØE17 pourrait participer à la genèse et/ou développement de ce lymphome. / Implication of ROQUIN in the physiopathology of angio-immunoblastic T cell lymphoma. AITL is a peripheral T cell lymphoma, poorly studied compared to B cell lymphomas due to its rarity. In France, AITL is the PTCL the most frequently encountered. Despite a variable clinical course, AITL is an aggressive tumor with an overall survival lower than 3 years. One of our goal is to better understand the physiopathology of this lymphoma and identify oncogenic events that lead to its development. In this project, our study was focused on ROQUIN gene that encodes a RING E3 ubiquitin ligase and whose mutation induces an AITL-like syndrom in sanroque mice.Although we did not detect any mutation in ROQUIN coding sequence, we identified a novel alternative transcript referred as ROQUIN ØE17. It encodes a protein that, like wild type protein, localizes to stress granules and P bodies and interacts with mRNAs and microRNAs. However, only ROQUIN ØE17 inhibits the expression of the costimulatory molecule ICOS. This transcript, whose expression varies between T cell populations, is hardly expressed in AITL. Consequently, the loss of ROQUIN ØE17 could be involved in the genesis and/or development of this lymphoma.

Le modèle murin le plus utilisé pour le diabète de type 1 est la souris NOD. L’activation des lymphocytes T autoréactifs vis à vis des cellules béta nécessite la reconnaissance par le TCR de l’auto antigène présenté par le CMH ainsi que des signaux de co stimulation. Nous apportons la preuve que la voie de costimulation ICOS/ICOSL est indispensable au développement du diabète chez la souris NOD. En effet, les souris invalidées pour le gène Icos ou IcosL sont protégées du diabète. Nous avons démontré que cette protection est liée à un défaut d’activation des LT diabétogènes. De façon inattendue, nous avons observé chez ces souris ICOS-/- et ICOSL-/- une neuromyopathie. Cette pathologie se développe parallèlement au diabète chez la souris ICOSL+/+. Sur le plan histologique, le muscle strié périphérique et le nerf périphérique est envahi par un infiltrat lymphocytaire et par des cellules présentatrices d’antigène. Nous avons démontré par des expériences de transfert adoptif que la neuromyopathie est une maladie auto-immune données, nous avons étudié les souris NOD ICOSL-/- CIITA-/-. Ces souris sont dépourvues de lymphocytes T -CD4+ et ne développent pas de neuromyopathie ni de diabète. De même, nous avons étudié les souris NOD ICOSL-/- béta2m-/-. Ces souris sont dépourvues de lymphocytes T-CD8+ et développent une neuromyopathie. Cette déviation de l’auto-immunité est liée à l’interaction entre les LT et les lymphocytes B via le signal ICOS/ICOSL. Nous avons prouvé via des expériences de transfert et de chimères que l’absence de signal ICOS/ICOSL entre les lymphocytes T et les lymphocytes B oriente l’auto-immunité vers le système nerveux périphérique et le muscle strié. Enfin, l’analyse du spectre de spécificité des anticorps présent chez la souris ICOSL-/- par western blot puis par spectrométrie de masse a précisé les cibles antigéniques de la myopathie. L’invalidation de la voie ICOS/ICOSL conduit donc à une déviation de l’auto-immunité du pancréas vers le muscle et le système nerveux périphérique. Ces données prouvent que la voie ICOS/ICOSL est indispensable à l’initiation du diabète, mais aussi au contrôle de l’auto-immunité / Costimulation pathways are described as central in T cell activation and the control of autoimmune responses. We previously reported that NOD mice that are deficient for the icosl gene are protected from diabetes, but instead develop a spontaneous autoimmune neuromyopathy. The general phenotype of the neuromyopathy observed in ICOSL-/- NOD mice is globally similar to that observed in ICOS-/- and ICOS-/-ICOSL-/- double knockout NOD mice. The neuromyopathy is observed in 100% of female mice by the age of 35 weeks. The neuropathy remains limited to the peripheral nerve tissue. The disease is characterized by an infiltration of immune cells: CD4+ T cells, CD8+ T cells, dendritic cells and B lymphocytes, but does not extend to the central nervous system. A similar infiltrate is seen in muscles. Autoimmune neuromyopathy can be transfer to naive recipients by T lymphocytes. Transfer is achieved in NOD.scid recipient mice by CD4+ T-cells, although not by CD8+ T-cells, isolated from 35 week old ICOSL-/- NOD. The predominant role of CD4+T-cells is further demonstrated in this model by the observation that CIITA-/-ICOSL-/- NOD mice do not developed the neuromyopathy. By contrast, ȕ2m-/-ICOSL-/- NOD mice develop a neuromyopathy. We obtained evidence (in chimeric mice) that the interaction between antigen-presenting cells (APC) and T lymphocytes via ICOS/ICOSL is a prerequisite to the development of diabetes, while the loss of the interaction between T lymphocytes and APC play a key role in the development of nervous and muscular autoimmunity. Finally, the spectrum analysis of antibodies specificity in mouse ICOSL-/- with Western blot and mass spectrometry indicated the antigenic targets of myopathy. Altogether, our data indicate that the deviation of autoimmunity in NOD mice from the pancreas to muscles and the peripheral nervous system in the absence of ICOS/ICOSL signal is dependent on the loss of the physiological interaction between T cells and APC