Laboratory of Intestinal Immunity
- Christophe Cellier
- Georgia Malamut
- Valérie Gaboriau-Routhiau
- Frank Ruemmele
- Pamela Schnupf
- Bénédicte Pigneur
- Nicolas Guégan
- Sabine Rakotobé
- Bernadette Bègue
- Corinne Lebreton
- Benoit Clément
- Fabienne Charbit-Henrion
- Marion Picard
- Aurélie Couesnon
- Roman Goguyer-Deschaumes
- Rémi Duclaux-Loras
- Iris Nkamba
- Sascha Cording
- Marianna Parlato
SCHULTHESS J Interleukin-15-Dependent NKp46(+) Innate Lymphoid Cells Control Intestinal Inflammation by Recruiting Inflammatory Monocytes Immunity 2012 37:108-121
KORNEYCHUK, N Interleukin 15 and CD4+ T Cells Cooperate to Promote Small Intestinal Enteropathy in Response to Dietary Antigen Gastroenterology 2013 2014 Apr;146(4):1017-27.
Lécuyer E, Rakotobe S, Lengliné-Garnier H, Lebreton C, Picard M, Juste C, Fritzen R, Eberl G, McCoy KD, Macpherson AJ, Reynaud CA, Cerf-Bensussan N, Gaboriau-Routhiau V. Segmented filamentous bacterium uses secondary and tertiary lymphoid tissues to induce gut IgA and specific T helper 17 cell responses. Immunity. 2014 Apr 17;40(4):608-20.
Schnupf P, Gaboriau-Routhiau V, Gros M, Friedman R, Moya-Nilges M, Nigro G, Cerf-Bensussan N, Sansonetti PJ. Growth and host interaction of mouse segmented filamentous bacteria in vitro. Nature. 2015 Apr 2;520(7545):99-103.
Ettersperger J. Interleukin 15- dependent T cell-like innate intraepithelial lymphocytes develop in the intestine and transform into lymphomas in celiac disease. Immunity. 2016.45:610-625
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See all the publications of the Imagine Institute
Laboratory of Intestinal Immunity
With a 300m2 surface, the intestine is the body’s main interface with the environment. This surface is indispensable for absorbing nutrients. It is also a tightly regulated barrier that has evolved in concert with the immune system to cope with the complex community of microbes that settle in the intestine after birth. This barrier function relies on multiple mechanisms, which cooperate to restrict body access to microbes and undigested food antigens while avoiding deleterious inflammation and tissue damage. Any deficiency can lead to severe intestinal diseases of either monogenic or polygenic inheritance. By dissecting these diseases but also by interrogating host-microbiota interactions, we expect to gain insight into intestinal immunoregulation, to define new diagnosis tools and to propose rationale-based therapeutic strategies.
1- Dissecting severe enteropathies in humans
A first axis of research concerns coeliac disease (CD). This frequent autoimmune-like disease is driven by chronic ingestion of gluten in genetically predisposed individuals. CD is generally cured by a strict gluten-free diet but severe complications can develop, notably irreversible autoimmune diseases and intestinal lymphomas. Based on the analysis of a large cohort of well-characterized patients, on in situ and exvivo analyses of human intestinal lymphocytes and on mouse models, we investigate mechanisms that drive intestinal tissue damage and lymphomagenesis. We have shown that interleukin 15 (IL-15) is a key player. This cytokine impairs local immunoregulation and cooperates with antigen-specfic CD4+ T cells to activate cytotoxic lymphocytes and tissue damage. IL-15 can also promote the onset of lymphomas from an unusual subset of innate-like lymphocytes. Our recent work further showed that i- the latter lymphocytes differentiate in the gut epithelium in response to sequential NOTCH and IL-15 signals; and ii- in CD, JAK1 or STAT3 somatic mutations enable their clonal expansion and transformation into lymphomas. We intend: i- to further dissect the genetic events that drive lymphomagenesis; and ii- to pursue on-going work on interactions between the CD71 receptor and SIgA-gluten complexes and their role in CD pathogenesis.
A second more recent axis of research led with the support of an ERC grant, is dedicated to the genetic dissection of Mendelian enteropathies. These rare but very severe diseases are caused by mono or biallelic mutations in genes with key roles in the intestinal barrier. They often start very early in life and resist to conventional treatments. Patients are recruited through collaborative networks in France (Immunobiota) and in Europe (GENIUS) and studied by combining functional analyses, custom made targeted gene panel sequencing and whole exome sequencing. A known Mendelian cause of enteropathy was identified in 33% of the 217 patients already investigated. Several novel candidate genes have been pinpointed. This work is pursued with the goals: i.- to identify human pathways indispensable for intestinal homeostasis; and ii.- to set up a diagnosis platform and improve the care of these life-threatening diseases.
2- Host-microbiota cross-talk and development of the intestinal barrier
It is now clear that the gut microbiota critically influences host metabolism and immune system, and that differences in the gut microbiota composition participate in the development of chronic inflammatory and allergic diseases. Based on analyses led in gnotobiotic mice, we have demonstrated the key role of Segmented Filamentous Bacterium (SFB) in the post-natal maturation of the gut immune barrier. An in vitro culture method has been developed to interrogate its mechanisms of action at the cellular and molecular levels. We further intend to define whether SFB is part of the human microbiota and if so, to define its impact on the intestinal immune barrier in health and diseases and investigate its potential use as a probiotic and a vaccinal platform.