Biomedical research institute
     
    You are here: Home / Departments / Endocrinology, Metabolism and Diabetes / Team A. Lehuen, R. Mallone

    Team: Immunology of diabetes

    •  

    Team leaders:


    Both innate (e.g. NKT, MAIT, dendritic cells) and adaptive (e.g. T lymphocytes) immune cells contribute to type 1 diabetes (T1D) pathogenesis. As dendritic cells act as “danger sensors” of the immune system, they first prompt activation of innate immune cells. Subsequent amplification of this stimulatory cascade focuses the (auto)immune response towards selected molecular targets (epitopes) by CD4+ and CD8+ T cells. Several regulatory mechanisms – including regulatory T cells – are bypassed at different stages of disease. Understanding these different steps in autoimmune progression is essential to elaborate immune surrogate markers for T1D risk assessment and follow-up; and to therapeutically divert autoimmunity towards tolerance restoration.

     Objectives

    We are investigating immune cell cross-talks involved in diabetes development and regulation taking advantages of our strong expertise on mouse models and our tight interactions with clinical departments. Our goal is to better understand the role of immune cells in both protective and deleterious functions in diabetes and to develop new preventative strategies. Our projects on the role of innate cells and autoreactive T cells may provide relevant targets for understanding disease mechanisms, discovering autoimmune biomarkers and developing antigen vaccination strategies.

    The ultimate goal is the combination of immune monitoring and intervention strategies to predict and prevent T1D onset in humans. Such strategies could offer a veritable shift in paradigm in the approach to T1D, as they would identify and correct immune pathogenesis rather than its metabolic consequences. The involvement of several investigators in the Diabetology clinic is an additional asset towards these translational goals. The recent establishment of the Departement Hospitalo-Universitaire (DHU) AutHors (Autoimmune and Hormonal Diseases) further strengthens the links between lab and clinic. The aims of our ongoing studies are:

    1) To determine the role of innate-like T cells in the regulation of both T1D and T2D . NKT and MAIT cells are non-conventional T cells that recognized lipids antigens and vitamin metabolites, respectively. As such they could be play a critical role as sensors of metabolic abnormalities. Importantly these innate-like T cells can regulate both innate and adaptive immunity. Our data obtained in several mouse models have demonstrated the efficacy of NKT cells in the prevention of T1D. NKT cells have also been involved in the regulation of metabolic diseases in mouse models. MAIT cells are present in various tissues and more particularly in the liver and colon, where they are activated by bacterial ligands. Due to the impact of microbiata in the development of T1D and T2D, we are presently analyzing the role of MAIT cells in both pathologies. These studies are performed in diabetic and obese patients as well as in mouse models using mice deficient or overexpressing MAIT cells.

    2) To clarify the mechanisms by which autoreactive T cells (Lien sous groupe RM) lead to destruction of pancreatic β cells. This requires to preliminarily identify the molecular targets (epitopes) exposed by β cells and driving T-cell recognition; and the T-cell receptors involved in such recognition. Such information allows us to develop cellular and molecular assays to track these rare lymphocytes in the blood of patients in order to stage autoimmune progression and response to immunotherapy. Preclinical mouse models are further used to test novel vaccination strategies selectively targeting autoreactive T cells without causing generalized immunosuppression. The technologies developed for the study of T1D autoimmunity are further applied to other relevant clinical setting, e.g. to select the most suitable vaccination strategies and to develop adoptive T-cell therapies for cancer and infectious diseases.

    3) To develop ‘humanized’ mouse models  more closely mimicking human T1D and to understand the role of costimulatory pathways in the autoimmune activation against a given self-tissue. Such models are instrumental for launching clinical trials exploring vaccination strategies with β-cell antigens aimed at restoring immune tolerance.

    4) To determine T1D susceptibility and protective genetic loci . Current work is focused on the circadian rhythm related gene Arntl2.  

     

    Main publicatons

    • Magalhaes I. K. Pingris, C. Poitou, S. Bessoles, N. Venteclef, B. Kiaf, L. Beaudoin, J. Da Silva, O. Allatif, J. Rossjohn, L. Kjer-Nielsen, J. McCluskey, S. Ledoux, L. Genser, A. Torcivia, C. Soudais, O. Lantz, C. Boitard, J. Aron-Wisnesky, E. Larger, K. Clément and A. Lehuen. Mucosal Associated Invariant T cell alterations in obese and type 2 diabetic patients. J. Clinical Investigation 2015, 125(4): 1752-62.
    • Diana J, Simoni Y, Furio L, Beaudoin L, Agerberth B, Barrat F, Lehuen A. Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes. Nat Med. 2013;19(1):65-73.
    • Scotto M, Afonso G, Østerbye T, Larger E, Luce S, Raverdy C, Novelli G, Bruno G, Gonfroy-Leymarie C, Launay O, Lemonnier FA, Buus S, Carel JC, Boitard C, Mallone R. HLA-B7-restricted islet epitopes are differentially recognized in type 1 diabetic children and adults and form weak peptide-HLA complexes. Diabetes. 2012;61(10):2546-55. 
    • Luce S, Lemonnier F, Briand JP, Coste J, Lahlou N, Muller S, Larger E, Rocha B, Mallone R, Boitard C. Single insulin-specific CD8+ T cells show characteristic gene expression profiles in human type 1 diabetes. Diabetes. 2011;60(12):3289-99.
    • Diana J, Brezar V, Beaudoin L, Dalod M, Mellor A, Tafuri A, von Herrath M, Boitard C, Mallone R, Lehuen A. Viral infection prevents diabetes by inducing regulatory T cells through NKT cell-plasmacytoid dendritic cell interplay. J Exp Med. 2011;208(4):729-45
    • Martinuzzi E, Afonso G, Gagnerault MC, Naselli G, Mittag D, Combadière B, Boitard C, Chaput N, Zitvogel L, Harrison LC, Mallone R. acDCs enhance human antigen-specific T-cell responses. Blood. 2011;118(8):2128-37.

     

     

    Team news


    Equipe FRM
    label 2014 of the Fondation Recherche Médicale

    Departement Hospitalo-Universitaire (DHU) label 2013

    Laboratory of Excellence Labex INFLAMEX (http://www.inflamex.fr)

    Awardee of the 2013 ‘Roger Assan’ Prize of the Societé Francophone du Diabète – C. Boitard

    Awardee of the 2012 ‘Apollinaire Bouchardat’ Prize – R. Mallone

    Awardee of the 2012 ‘Morgagni Young Investigator Award’ – R. Mallone

    Multimedia-Interview “LCI Santé” with Alain Ducardonnet, January 201

    Team’s patents :

    • European patent PCT/EP14305080.5 “Methods for testing T cell priming efficacy in a subject”. Inventors V. Appay, R. Mallone, A. Lissina.
    • European patent PCT/EP13305530 “Method for stimulating antigen-specific T cell responses”. Inventors R. Mallone, G. Afonso.
    • European patent PCT/EP12790977.8 “Use of Mycobacterium avium paratuberculosis peptides to diagnose type 1 diabetes”. Inventors L.A. Sechi, R. Mallone.
    • European patent PCT/EP2012/056365 « Culture Medium and Methods for obtaining a population of tolerogenic dendritic cells ». Inventors H. Hocini, R. Monteiro, H. Bouhlal, A. Lehuen, J. Diana.
    • International patent WO/2010/119033 “Method for stimulating antigen-specific T cell responses using accelerated co-cultured dendritic cells”. Inventors R. Mallone, E. Martinuzzi.