Die Rolle von tertiären lymphatischen Geweben bei Entzündungsreaktionen und entzündlichen Erkrankungen im Darm
Final Report Abstract
The de novo organization of spatially and structurally organized aggregations of leucocytes into tertiary lymphoid tissues (tLTs) has been described in conditions of chronic inflammation, as well as bacterial or viral infection in human and mice. Bacterial colonization of the murine intestine also leads to the induction of tertiary lymphoid tissues (isolated lymphoid follicles ILF). Recently, RORγt expressing lymphoid inducer (LTti) cells, required for lymphnode and Peyer’s patch development in the fetus, have been shown to be essential for the formation of ILFs. The aim of this project was to study the formation and role of tLTs during intestinal inflammation and to elucidate the role for Lti cells in this process. To this end, I used the chronic Dextran sulfate sodium (DSS) induced colitis mouse model in transgenic mice that express EGFP under the control of the Rorc(γt) locus. In these RORγt– EGFP mice, DSS treatment leads to a strong increase in the number of mature and immature ILFs in the colon. In addition, de novo formation of tLT in the intestine is not possible in the absence of RORγt+ Lti cells, proving the unique importance of these cells for the initiation of lymphoid follicle development in the intestine. In the second part of this project, I could identify a subset of CD3+ T cells expressing RORγt. In RORγt-EGFP mice, about half of the RORγt+ cells express the cytokine IL- 17. In addition, RORγt+ T cells include regulatory Foxp3+ T cells that express the cytokine IL-10. I could further show, that these subsets coexist in a tightly controlled equilibrium. Pertubation in this equilibrium might lead to decreased immunoreactivity or, in contrast, to pathological inflammation.
Publications
- Critical role of ROR-γt in an alternative thymic pathway that induces IL-17-producing iNKT cell differentiation. Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19845-50
Marie-Laure Michel, Daniella Mendes da Cruz, Alexandre Castro Keller, Matthias Lochner, Elke Schneider, Michel Dy, Gérard Eberl, and Maria C. Leite-de-Moraes
- Dendritic cells activated via dectin-1 convert regulatory T cells into IL-17 producers. Eur J Immunol. 2008 Dec;38(12):3274-81
Fabiola Osorio, Salomé LeibundGut-Landmann, Matthias Lochner, Katharina Lahl, Tim Sparwasser, Gérard Eberl, and Caetano Reis e Sousa
- In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgamma t+ T cells. J Exp Med. 2008 Jun 9;205(6):1381-93
Lochner M, Peduto L, Cherrier M, Sawa S, Langa F, Varona R, Rieth1macher D, Si- Tahar M, Di Santo JP, Eberl G
- Microbial Flora Drives Interleukin 22 Production in Intestinal NKp46(+) Cells that Provide Innate Mucosal Immune Defense. Immunity. 2008 Dec;29(6):958-70
Satoh-Takayama N, Vosshenrich CA, Lesjean-Pottier S, Sawa S, Lochner M, Rattis F, Mention JJ, Thiam K, Cerf-Bensussan N, Mandelboim O, Eberl G, Di Santo JP
