|Lymphoid Tissue Development - CNRS URA 1961|
|HEAD||Dr. EBERL Gérard / firstname.lastname@example.org|
|MEMBERS||Dr. PEDUTO Lucie / Postdoc Dr. LOCHNER Matthias / Postdoc Dr. SAWA Shinichiro / Postdoc Dr. CHERRIER Marie / Postdoc BOUSKRA Djahida / Ph.D. Student POLOMACK Bernadette / Technician DULAUROY Sophie / Technician HUGOT Bérangère / Administrative Assistant
Adaptive immune responses are initiated in large and highly organized clusters of lymphocytes and antigen presenting cells, the secondary and tertiary lymphoid tissues (LTs). The development of secondary LTs (lymph nodes and Peyer’s patches) is programmed and initiated in the sterile environment of the fetus. A cascade of events is triggered by lymphoid tissue inducer (LTi) cells, which recapitulates the inflammatory reaction and culminates in the formation of complex structures carrying both specialized hematopoietic and stromal cells. The formation of tertiary LTs (tLTs) follows a similar pathway, but is induced after birth by commensal microbes, infection or injury. Chronic inflammation also leads to the spatial organization of the lesion and formation of tLTs, which establish a positive feedback loop of lymphocyte activation. The aim of our laboratory is to understand the mechanisms that lead to the formation of LTs, during fetal life, in response to intestinal commensals, during infection and injury, and during the inflammatory reaction. The long-term goal is to develop new and specific tools for the control of chronic inflammatory disease, such as inflammatory bowel disease or rheumatoid arthritis, or conversely, to induce the formation of LTs to enhance local immunity against infection or cancer.
1. The development of lymphoid tissues
Many factors involved in inflammation, such as the cytokines TNF, lymphotoxin, the chemokines CCL19, CCL21 and CXCL13 and the adhesion molecules ICAM-1 and VCAM-1, need to be expressed in the sterile environment of the fetus for lymph nodes and Peyer's patches to develop. We have generated BAC-transgenic mice to visualize and isolate the cellular and molecular actors involved in the development of lymphoid tissues and inflammation, and to assess the impact of these actors in autoimmune, infectious and tumor pathology. One of these mice expresses the fluorescent protein GFP under control of the Rorc(γt) locus (Rorc(γt)-GfpTG mice), labeling fetal and adult lymphoid tissue inducer (LTi) cells.
2. Lymphoid stromal cells
Lymphoid stromal (LS) cells organize the fetal development of lymphoid tissues by recruiting LTi cells and lymphocytes at specific time points and locations during ontogeny. These cells express structural chemokines, adhesion molecules and cytokines that are required to stabilize the lymphoid structure into adulthood. During inflammation, LS cells are induced by neutrophils and recapitulate the ontogeny of lymphoid tissues when the inflammation persists. Using BAC-transgenic mice, different subsets of LS cells are identified, isolated and characterized to understand, more generally, the role of stromal cells in immunity.
3. RORγt+ cells
The nuclear hormone receptor RORγt is necessary for the development of LTi cells. In the absence of RORγt, LTi cells are not generated and lymph nodes and Peyer's patches fail to develop. RORγt is also expressed by immature CD4+CD8+ T cells in the thymus. Furthermore, RORγt opens a pro-inflammatory differentiation program in a variety of mature lymphoid cells, including αβ T cells, γδ T cells, invariant NKT cells and NKp46+ cells. In all these cell types, RORγt is associated with the expression of IL-17 or IL-22, cytokines involved in the pro-inflammatory Th17 pathway and epithelial defense. Using the BAC-transgenic Rorc(γt)-GfpTG mice, we dissect the development and the role of these RORγt+ cells in ontogeny, homeostasis and inflammation.
4. Intestinal homeostasis
After birth, LTi-like cells are clustered as cryptopatches in the intestinal lamina propria. Cryptopatches are sensors of the bacterial flora and induce the formation of isolated lymphoid follicles (ILFs) through the recruitment of naïve B cells. We have found that peptidoglycans shed by Gram-negative bacteria are recognized by the innate receptor NOD1 in epithelial cells, which then induce the production of the chemokine CCL20 and the β defensin-3, and the activation of LTi-like cells and B cells through CCR6. This mechanism of bacteria-induced lymphoid tissue formation culminates in the production of IgA that target the bacterial community, thereby establishing a negative feedback loop and regulating intestinal homeostasis. These findings suggest that peptidoglycans might be used to modulate intestinal inflammatory disease.
A cryptopatch (left, 400x) and an ILF (right, 100x) in mouse adult intestine. LTi cells (green), DCs (red) and B cells (blue).
Keywords: Lymphoid tissues, inflammation, lymphoid stromal cells, intestinal homeostasis, Th17 cells
D. Bouskra, C. Brézillon, M. Bérard, C. Werts, R. Varona, I. Gomperts Boneca, and G. Eberl. 2008. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature, 456:507-510.
N. Satoh-Takayama, C.A.J. Vosshenrich, S. Lesjean-Pottier, S. Sawa, M. Lochner, F. Rattis, J.J. Mention, K. Thiam, N. Cerf-Bensussan, O. Mandelboim, G. Eberl and J.P. Di Santo. 2008. Microbial flora drives interleukin 22 production in NKp46+cells that provide innate mucosal immune defense. Immunity, 29:958-970.
M. Lochner, L. Peduto, M. Cherrier, S. Sawa, F. Langa, R. Varona, D. Riethmacher, M. Si-Tahar, J.P. Di Santo, and G. Eberl. 2008. In vivo Equilibrium of pro-inflammatory IL-17+and regulatory IL-10+Foxp3+ RORγt+T cells. J. Exp. Med., 205:1381-1393.
G. Eberl. 2007. From induced to programmed lymphoid tissues: the long road to pre-empt pathogens. Trends in Immunology, 28:423-428.
G. Eberl. 2005. Inducible lymphoid tissues in the adult gut: recapitulation of a fetal developmental pathway? Nat. Rev. Immunol., 5:413-420.
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