Nadine Cerf-Bensussan

Pathogenesis of severe human enteropathies

1. Coeliac disease (CD): is a long-standing axis of research  for our team, which coordinates a National INCA network for diagnosis and treatment of complicated CD. This frequent autoimmune-like disease is driven by chronic ingestion of wheat-derived gluten in genetically predisposed individuals. . Based on the analysis of a large cohort of well-characterized patients, on in situ and ex vivo analyses of human intestinal lymphocytes and on mouse models, we investigate the 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-specific CD4+ T cells to activate cytotoxic lymphocytes and tissue damage. IL-15 can also promote the onset of lymphomas from an unusual subset of lymphocytes that we have identified in the gut epithelium. The latter lymphocytes differentiate locally from bone marrow-derived precursors in response to sequential NOTCH and IL-15 signals. NOTCH signals initiate T cell differentiation, revealed by expression of intracellular CD3 (iCD+) and evidence of T cell receptor rearrangements. IL-15 induces Granzyme B, a protease that cleaves NOTCH into a peptide deprived of transcriptional activity. As a consequence, T cell differentiation is prematurely stopped. Cells are redirected by default toward the NK pathway and acquire NK markers and function. While innate-like iCD3+ lymphocytes form a minor polyclonal subset of lymphocytes in the normal adult gut epithelium, their massive clonal expansion is a diagnosis hallmark of CD-associated lymphomas. Strikingly, in many cases, malignant innate-like T cells display gain of function somatic mutations in JAK1 and or STAT3, which confer a selective advantage in the cytokine (IL-15-) rich environment of the coeliac intestine. Our present work aims at further dissecting the mechanisms that drive malignant transformation and progression from low- to high-grade lymphomas and at using these results to improve diagnostic and therapeutic strategies.

The gut microbiota has emerged as a key determinant in health and disease. One outstanding challenge is now to identify which members of the microbiota are indispensable to promote host fitness and to delineate their mechanisms of action. Based on analyses led in gnotobiotic mice, we have demonstrated that Segmented Filamentous Bacterium (SFB) is indispensable to drive the post-natal maturation of the mouse gut immune barrier. SFB is notably a potent inducer of secondary and tertiary gut lymphoid tissue. It strongly stimulates IgA secretion and intestinal T cells and, most strikingly, is indispensable to launch gut homeostatic TH17 responses. Unlike other commensals, which typically reside in the intestinal lumen and have limited access to the intestinal surface, SFB is unique in that it intimately attaches to ileal epithelial cells. This attachment is species-specific, suggesting a co-evolutionary symbiosis between SFB and its many vertebrate hosts. Based on the hypothesis that SFB growth requires direct contact with live epithelial cells, we have developed a method for in vitro culture of SFB, which allows to recapitulate its very characteristic life and to induce a transcriptomic epithelial response similar to that observed in vivo. Thus, attachment allows SFB access to host resources indispensable for its growth. Conversely, colonization of SFB does not lead to pathology but induces as yet poorly defined signals, which stimulate innate and adaptive immunity. Our goals are now to Identify the mechanisms of SFB stimulation at the cellular and molecular levels, 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 with the long term goal to develop SFB into a probiotic and or a vaccinal platform.