HLA-Class II Artificial Antigen Presenting Cells in CD4+ T Cell-Based Immunotherapy

CD4+ T cells differentiate into various T helper subsets characterized by distinct cytokine secreting profiles that confer them effector functions adapted to a variety of infectious or endogenous threats. Regulatory CD4+ T cells are another specialized subset that plays a fundamental role in the maintenance of immune tolerance to self-antigens. Manipulating effector or regulatory CD4+ T cells responses is a promising immunotherapy strategy for, respectively, chronical viral infections and cancer, or severe autoimmune diseases and transplantation. Adoptive cell therapy (ACT) is an emerging approach that necessitates defining robust and efficient methods for the in vitro expansion of antigen-specific T cells then infused into patients. To address this challenge, artificial antigen presenting cells (AAPCs) have been developed. They constitute a reliable and easily usable platform to stimulate and amplify antigen-specific CD4+ T cells. Here, we review the recent advances in understanding the functions of CD4+ T cells in immunity and in immune tolerance, and their use for ACT. We also describe the characteristics of different AAPC models and the way to improve their stimulating functions. Finally, we discuss the potential interest of these AAPCs, both as fundamental tools to decipher CD4+ T cell responses and as reagents to generate clinical grade antigen-specific CD4+ T cells for immunotherapy

Etude des relations immunitaires hôte-tumeur dans le cancer de l'ovaire

RENNES1-BU Santé (352382103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Les récepteurs de nectines/ nectines-like DNAM-1 et CRTAM [Nectins and nectin-like receptors DNAM-1 and CRTAM: new ways for tumor escape]

National audienceNectin and nectin-like (Necl) are cell adhesion molecules expressed in various tumors. They were alternatively reported as involved in tumor suppressor or oncogenic functions that led to their use as histological or serological cancer markers. Gene inactivation in lung carcinoma but overexpression in leukemia were reported for Necl-2. DNAM-1 and CRTAM are emerging NK receptors of immune cells that were described to interact with nectin and Necl. DNAM-1, constitutively expressed by CD8(+) T cells, NK or γδ T lymphocytes, is a ligand of Necl-5. It participates to tumor immunosurveillance promoting Necl-5 expressing tumor cell lysis. CRTAM, only expressed after lymphocyte activation, is a ligand of Necl-2. Engagement of CRTAM with Necl-2 has opposite effects depending on the type of lymphocyte. For NK or CD8(+) T cells, it promotes cytotoxicity and IFNγ secretion favoring immunosurveillance. By contrast, CRTAM/Necl-2 interaction triggers cell death of activated TVg9Vd2 γδ T cells favoring immune escape. Nectin and Necl-mediated interactions appear to be crucial for the delicate balance between tumor escape and antitumor response

Mécanismes de la lymphopénie radio-induite et implications thérapeutiques

International audienceLa lymphopénie radio-induite est fréquente et peut être profonde et durable. Bien que les lymphocytes soient connus depuis longtemps comme des cellules très radiosensibles, la lymphopénie radique est mal caractérisée. La lymphopénie radio-induite semble affecter différemment les sous-populations de lymphocytes et semble être influencée par les modalités de radiation. La profondeur et la durée de la lymphopénie sont variables selon la localisation de l’irradiation et les volumes de traitement. La lymphopénie radio-induite a été associée à un pronostic plus défavorable dans plusieurs types de tumeurs. Une connaissance plus approfondie de la lymphopénie radio-induite pourrait amener à repenser les modalités de la radiothérapie et à des approches pour restaurer le taux de lymphocytes

Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases

The excitatory neurotransmission of the central nervous system (CNS) mainly involves glutamate and its receptors, especially N-methyl-D-Aspartate receptors (NMDARs). These receptors have been extensively described on neurons and, more recently, also on other cell types. Nowadays, the study of their differential expression and function is taking a growing place in preclinical and clinical research. The diversity of NMDAR subtypes and their signaling pathways give rise to pleiotropic functions such as brain development, neuronal plasticity, maturation along with excitotoxicity, blood-brain barrier integrity, and inflammation. NMDARs have thus emerged as key targets for the treatment of neurological disorders. By their large extracellular regions and complex intracellular structures, NMDARs are modulated by a variety of endogenous and pharmacological compounds. Here, we will present an overview of NMDAR functions on neurons and other important cell types involved in the pathophysiology of neurodegenerative, neurovascular, mental, autoimmune, and neurodevelopmental diseases. We will then discuss past and future development of NMDAR targeting drugs, including innovative and promising new approaches

HLA-Class II Artificial Antigen Presenting Cells in CD4+ T Cell-Based Immunotherapy

International audienc

Lymphocytes Tγδ en cancérologie

Les lymphocytes Tγδ présentent à la fois des caractéristiques de cellules de l’immunité innée et de l’immunité adaptative. Ils expriment le récepteur de reconnaissance des antigènes TCR associé au complexe CD3 - mais sa diversité est moindre que celle du TCR des lymphocytes Tαβ - et n’expriment que rarement CD4 ou CD8. Chez l’homme, la sous-population majoritaire dans le sang est de type T Vγ9Vδ2. Les T Vγ9Vδ2 peuvent lyser les cellules tumorales en reconnaissant à leur surface de petits métabolites phosphorylés, les phosphoantigènes (PAg). Ces molécules et leurs analogues synthétiques (Phosphostim™) permettent de nouvelles stratégies thérapeutiques fondées sur les lymphocytes Tγδ, décrits dans cet article

Tissue-plasminogen activator effects on the phenotype of splenic myeloid cells in acute inflammation

Abstract Tissue-plasminogen activator (tPA) is a serine protease well known for its fibrinolytic function. Recent studies indicate that tPA could also modulate inflammation via plasmin generation and/or by receptor mediated signalling in vitro. However, the contribution of tPA in inflammatory processes in vivo has not been fully addressed. Therefore, using tPA-deficient mice, we have analysed the effect of lipopolysaccharide (LPS) challenge on the phenotype of myeloid cells including neutrophils, macrophages and dendritic cells (DCs) in spleen. We found that LPS treatment upregulated the frequency of major histocompatibility class two (MHCII+) macrophages but also, paradoxically, induced a deep downregulation of MHCII molecule level on macrophages and on conventional dendritic cells 2 (cDC2). Expression level of the CD11b integrin, known as a tPA receptor, was upregulated by LPS on MHCII+ macrophages and cDC2, suggesting that tPA effects could be amplified during inflammation. In tPA−/− mice under inflammatory conditions, expression of costimulatory CD86 molecules on MHCII+ macrophages was decreased compared to WT mice, while in steady state the expression of MHCII molecules was higher on macrophages. Finally, we reported that tPA deficiency slightly modified the phenotype of DCs and T cells in acute inflammatory conditions. Overall, our findings indicate that in vivo, LPS injection had an unexpectedly bimodal effect on MHCII expression on macrophages and DCs that consequently might affect adaptive immunity. tPA could also participate in the regulation of the T cell response by modulating the levels of CD86 and MHCII molecules on macrophages

Immunostimulatory properties of dendritic cells after Leishmania donovani infection using an in vitro model of liver microenvironment.

International audienceBACKGROUND: Recent advances demonstrated that liver dendritic cells (DCs) promote immunologic hyporesponsiveness that may contribute to hepatic tolerance. Although there has been significant work on the phenotypic and functional roles of such DCs, the impact of liver microenvironment on the immune properties of infected DC is still poorly explored, probably because of the limitations of modelization. METHODOLOGY/PRINCIPAL FINDINGS: Here, we hypothesized that DC tolerogenic properties have an impact on the antimicrobial response, particularly during the infection by the protozoan parasite Leishmania donovani. Indeed, a lymphocytic Th2 environment was reported to favour the growth and proliferation of L. donovani. We first modelized an adequate monocyte-differentiated DC model, either in rat liver epithelial cell- or in a human hepatic non-parenchymal cell-conditioned medium in order to infect them further. We established that DCs differentiated in a hepatic microenvironment displayed a CD14+/CD16+/CD123+ phenotype, secreted low IL-12p70 and had an impaired capacity to stimulate allogeneic T lymphocyte proliferation and IFNgamma secretion. We then infected DCs with L. donovani in the in vitro-defined hepatic microenvironment. The infection of hepatic DCs restored their capacity to stimulate allogeneic T-cell proliferation and to induce lymphocytic secretion of IFNgamma. Such characteristics were recently shown to favour granuloma formation in mice liver. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the specific immunostimulatory properties of infected hepatic DCs might amplify the granuloma maturation, which warrants the effective control of infection in the liver during visceral leishmaniasis