OX40 is required for regulatory T cell–mediated control of colitis

The immune response in the gastrointestinal tract is a tightly controlled balance between effector and regulatory cell responses. Here, we have investigated the role of OX40 in influencing the balance between conventional T cells and Foxp3+ regulatory T (T reg) cells. Under steady-state conditions, OX40 was required by T reg cells for their accumulation in the colon, but not peripheral lymphoid organs. Strikingly, under inflammatory conditions OX40 played an essential role in T reg cell–mediated suppression of colitis. OX40−/− T reg cells showed reduced accumulation in the colon and peripheral lymphoid organs, resulting in their inability to keep pace with the effector response. In the absence of OX40 signaling, T reg cells underwent enhanced activation-induced cell death, indicating that OX40 delivers an important survival signal to T reg cells after activation. As OX40 also promoted the colitogenic Th1 response, its expression on T reg cells may be required for effective competition with OX40-dependent effector responses

Rôle immunorégulateur des lymphocytes TNK dans le diabète de type 1 et les infections virales

Les lymphocytes TNK sont des lymphocytes T non conventionnels. Ils expriment un TCR avec une chaîne a invariante Va14 et des marqueurs associés aux cellules NK. Ils reconnaissent la molécule de classe I non-classique CD1d qui présente des glycolipides endogènes et exogènes. Fonctionnellement, ils sont capables de sécréter rapidement de grandes quantités de cytokines comme l IL-4 et l IFNg et possèdent des capacités immunostimulatrices et immunosuppressives. Les lymphocytes TNK sont impliqués dans les réponses anti-infectieuses et anti-tumorales. Ils jouent également un rôle protecteur dans plusieurs maladies autoimmunes. Le diabète de type 1 est une maladie autoimmune qui est associée à la destruction des cellules pancréatiques productrices d insuline par des lymphocytes T autoréactifs. Plusieurs travaux ont rapporté un effet protecteur des lymphocytes TNK dans le diabète de type 1, dans le cadre de modèles polyclonaux ou d un modèle monoclonal CD4. Dans la première partie de cette thèse, nous avons étudié l influence des lymphocytes TNK dans le cadre d un transfert monoclonal de lymphocytes T CD8 anti-îlots. Les lymphocytes TNK dans ce modèle ne sont pas capables d inhiber la réaction autoimmune, mais au contraire ils aggravent la maladie en stimulant la réponse destructrice des lymphocytes T CD8 anti-îlots.PARIS5-BU-Necker : Fermée (751152101) / SudocSudocFranceF

NKT cell-plasmacytoid dendritic cell cooperation via OX40 controls viral infection in a tissue-specific manner.

International audienceInvariant natural killer T (iNKT) cells promote immune responses to various pathogens, but exactly how iNKT cells control antiviral responses is unclear. Here, we showed that iNKT cells induced tissue-specific antiviral effects in mice infected by lymphocytic choriomeningitis virus (LCMV). Indeed, iNKT cells inhibited viral replication in the pancreas and liver but not in the spleen. In the pancreas, iNKT cells expressed the OX40 molecule and promoted type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) through OX40-OX40 ligand interaction. Subsequently, this iNKT cell-pDC cooperation attenuated the antiviral adaptive immune response in the pancreas but not in the spleen. The dampening of pancreatic anti-LCMV CD8(+) T cell response prevented tissue damage in transgenic mice expressing LCMV protein in islet beta cells. Thus, this study identifies pDCs as an essential partner of iNKT cells for mounting an efficient, nondeleterious antiviral response in peripheral tissue

Granulocyte macrophage colony-stimulating factor-activated eosinophils promote interleukin-23 driven chronic colitis

SummaryThe role of intestinal eosinophils in immune homeostasis is enigmatic and the molecular signals that drive them from protective to tissue damaging are unknown. Most commonly associated with Th2 cell-mediated diseases, we describe a role for eosinophils as crucial effectors of the interleukin-23 (IL-23)-granulocyte macrophage colony-stimulating factor (GM-CSF) axis in colitis. Chronic intestinal inflammation was characterized by increased bone marrow eosinopoiesis and accumulation of activated intestinal eosinophils. IL-5 blockade or eosinophil depletion ameliorated colitis, implicating eosinophils in disease pathogenesis. GM-CSF was a potent activator of eosinophil effector functions and intestinal accumulation, and GM-CSF blockade inhibited chronic colitis. By contrast neutrophil accumulation was GM-CSF independent and dispensable for colitis. In addition to TNF secretion, release of eosinophil peroxidase promoted colitis identifying direct tissue-toxic mechanisms. Thus, eosinophils are key perpetrators of chronic inflammation and tissue damage in IL-23-mediated immune diseases and it suggests the GM-CSF-eosinophil axis as an attractive therapeutic target