Institut de recherche biomédicale
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    Equipe : Immunologie du diabète


    Responsable :


    Diabetes is characterized by chronic hyperglycemia in patients causing serious vascular complications that lead to an increased risk of cardiovascular events, heart failure, kidney failure and loss of vision. The World Health Organization estimates 422 million people with diabetes worldwide. Type 1 diabetes, or insulin-dependent diabetes, accounts for about 10% of all cases, and in most of the patients it occurs before the age of 20. Type 2 diabetes, often associated with obesity, is declared later and concerns about 90% of the cases. Since this number is still increasing it is fundamental to better understand the disease mechanisms to develop new preventative and therapeutic strategies.



    We are investigating immune cell cross-talks involved in diabetes development and regulation, taking advantages of our strong expertise on mouse models and the tight interactions with several clinical departments. Our research is focussed on the role of the adaptive and innate immune cells in T1D and T2D diabetes/obesity. We particularly study Mucosal-Associated Invariant T (MAIT) cells and T-lymphocytes. We are also interested in the genetic pathways modulating pathologic development. Our goal is to better understand the role the protective and deleterious functions of the immune cells in diabetes and obesity. Our projects on innate cells and auto-reactive T cells may provide relevant targets for understanding disease mechanisms, discovering biomarker and developing innovative therapeutic strategies. The specific aims of our ongoing studies are:

    1) To determine the role of innate-like T cells in the regulation T1D. NKT and MAIT cells are non-conventional T cells that act as sensors of metabolic abnormalities.  These innate-like T cells can regulate both innate and adaptive immunity. Our data demonstrated the efficacy of both NKT and MAIT cells in the prevention of T1D.

    2) To determine the role of innate-like T cells in the regulation of T2D, obesity and non-alcoholic liver steatosis. We have recently shown that In T2D and obese patients circulating MAIT cells are altered and produce high levels of inflammatory cytokines in the adipose tissue. Together with our collaborators we showed that MAIT cells are profibrogenic in the liver of nonalcoholic steatohepatitis (NASH)-related cirrhotic patients.

    3) To develop ‘humanized’ mouse models more closely mimicking human T1D and to understand the role of co-stimulatory 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 genes and pathways involved in the diversity of juvenile-onset diabetes, from multifactorial T1D to monogenic forms of diabetes whose clinical presentation may be atypical or not.


    Main publications

    Philippi A, Heller S, Costa IG, Senée V, Breunig M, Li Z, Kwon G, Russell R, Illing A, Lin Q, Hohwieler M, Degavre A, Zalloua P, Liebau S, Schuster M, Krumm J, Zhang X, Geusz R, Benthuysen JR, Wang A, Chiou J, Gaulton K, Neubauer H, Simon E, Klein T, Wagner M, Nair G, Besse C, Dandine-Roulland C, Olaso R, Deleuze JF, Kuster B, Hebrok M, Seufferlein T, Sander M, Boehm BO, Oswald F, Nicolino M, Julier C, Kleger A. Mutations and variants of ONECUT1 in diabetes. Nat Med. 2021 Nov;27(11):1928-1940. doi: 10.1038/s41591-021-01502-7. Epub 2021 Oct 18. PMID: 34663987.
    Flament H.*, M. Rouland*, L. Beaudoin*, A. Toubal*, L. Bertrand, S. Lebourgeois, C. Rousseau, P. Soulard, Z. Gouda, L. Cagninacci, A. C. Monteiro, M. Hurtado-Nedelec, S. Luce, K. Bailly, M. Andrieu, B. Saintpierre, F. Letourneur, Y. Jouan, M. Si-Tahar, T. Baranek, C. Paget, C. Boitard, A. Vallet-Pichard, J-F. Gautier, N. Ajzenberg, B. Terrier, F. Pène, J. Ghosn, X. Lescure, Y. Yazdanpanah, B. Visseaux, D. Descamps, J-F. Timsit, R. C. Monteiro and A. Lehuen. Outcome of SARS-CoV-2 infection is linked to MAIT cell activation and cytotoxicity. Nature Immunology 2021 doi/10.1038/s41590-021-00870-z
    Rouland M.*, L. Beaudoin*, O. Rouxel*, L. Bertrand*, L. Cagninacci, A. Saffarian, T. Pedron, D. Gueddouri, S. Guilmeau, A-F. Burnol, L. Rachdi, A. Tazi, J. Mouriès, M. Rescigno, N. Vergnolle, P. Sansonetti, U. C. Rogner and A. Lehuen.
    Gut mucosa alterations and loss of segmented filamentous bacteria in type 1 diabetes are associated with inflammation rather than hyperglycemia. Gut 2021 doi:10.1136/gutjnl-2020-323664
    Nel I., L. Bertrand, A. Toubal and A. Lehuen. MAIT cells, guardians of skin and mucosa? Mucosal Immunology
    Toubal A, Kiaf B, Beaudoin L, Cagninacci L, Rhimi M, Fruchet B, da Silva J, Corbett AJ, Simoni Y, Lantz O, Rossjohn J, McCluskey J, Lesnik P, Maguin E, Lehuen A. Mucosal-associated invariant T cells promote inflammation and intestinal dysbiosis leading to metabolic dysfunction during obesity. Nat Commun. 2020 Jul 24;11(1):3755. doi: 10.1038/s41467-020-17307-0.
    Hegde P, Weiss E, Paradis V, Wan J, Mabire M, Sukriti S, Rautou PE,Albuquerque M, Picq O, Gupta AC, Ferrere G, Gilgenkrantz H, Kiaf  B, Toubal A, Beaudoin L, Lettéron P, Moreau R, Lehuen A*, Lotersztajn S*. (*co-last authors) Mucosal-associated invariant T cells are a profibrogenic immune cell population in the liver. Nature Communications 2018 Jun 1;9(1):2146.
    Luce S, Guinoiseau S, Gadault A, Letourneur F, Blondeau B, Nitschke P, Pasmant E, Vidaud M, Lemonnier F, Boitard C. A Humanized Mouse Model to Study Type 1 Diabetes.  Diabetes. 2018 Sep;67(9):1816-1829.
    Rouxel O, Da Silva J, Beaudoin L, Nell  I, Tard C, Cagnicacci L, Kiaf  B, Oshima M, Diedisheim M, Salou M, Corbett A, Rossjohn J, McCluskey J, Scharfmann R, Battaglia M, Polak M, Lantz O, Beltrand J, Lehuen A. Cytotoxic and regulatory roles of mucosal-associated invariant T cells in type 1 diabetes. Nature Immunology 2017 Dec;18(12):1321-1331.
    Dos Santos RS*, Daures M*, Philippi A*, Romero S, Marselli L, Marchetti P, Senée V, Bacq D, Besse C, Baz B, Marroquí L, Ivanoff S, Masliah-Planchon J, Nicolino M, Soulier J, Socié G, Eizirik DL, Gautier J-F, Julier C. (*: co-first authors) dUTPase (DUT) is Mutated in a Novel Monogenic Syndrome with Diabetes and Bone Marrow Failure. Diabetes 66:1086-1096, 2017
    Magalhaes I, Pingris K, Poitou C, Bessoles S, Venteclef N, KIAF B, Beaudoin L, Da Silva J, Allatif O, Rossjohn J, Kjer-Nielsen L, McCluskey J, Ledoux S, Genser  L, Torcivia A, Soudais C, Lantz O, Boitard C, Aron-Wisnewsky J, Larger E, Clément K, Lehuen A. Mucosal-associated invariant T cell alterations in obese and type 2  diabetic patients. Journal of Clinical Investigation 2015 Apr;125(4):1752-62.
    Lebailly B, He C, Rogner UC. Linking the circadian rhythm gene Arntl2 to interleukin 21 expression in type 1 diabetes. Diabetes 2014 Jun;63(6):2148-57.

    Team news

    2019 - Label "Equipe FRM"
    2018 - Award of the Fondation Francophone pour la Recherche sur le Diabète
    2018 - Network on MAIT cells in type 1 diabetes (ANR Diab1MAIT)
    2017 - Network Research Hospital-University in Health (RHU QUID NASH)
    2015 - Network on MAIT cells in type 2 diabetes and obesity (ANR OBEMAIT and PROVIDE)
    2013 - Network Department Hospital-University on autoimmunity (DHU AUTHORS)
    2011 - Executive committee of the Laboratory of Excellence (Labex) INFLAMEX


    Team’s patents

    • Methods and kits of assessing status, risk or prognosis of type 1 diabetes. WO 2017/162759, the 22nd March 2017 J. Da Silva, I. Nel, L. Beaudoin, A. Lehuen
    • Methods and pharmaceutical compositions for the treatment fibrosis with agents capable of inhibiting the activation of mucosal-associated invariant (MAIT) cells. PCT/FR2017/0, the 22nd June 2017 P. Hegde, E. Weiss, V. Paradis, A. Lehuen, S. Lotersztajn
    • Methods for predicting whether a subject suffering from a cardiometabolic disease is at risk of progression toward heart failure. PCT/FR 17 306 257.1, the 25th September 2017 A. Lehuen, S. André, K. Clement
    • Methods for the diagnosis and treatment of type 1 diabetes. EP155250, February 19th 2015. S. Luce and C. Boitard