Lymphoid Tissue Development - CNRS URA 1961  


  HEADDr. EBERL Gérard / geberl@pasteur.fr
  MEMBERSDr. 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


  Annual Report

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 secondary lymphoid tissues

In the fetus, lymphoid tissue inducer (LTi) cells are recruited to sites of LT development through the action of chemokines and integrins. LTi cells activate the local lymphoid stromal (LS) cells through membrane lymphotoxin LTα1β2 binding the LTβR, and induce the expression of additional chemokines and adhesion molecules. We have previously characterized a nuclear hormone receptor, RORγt, which is specifically expressed by LTi cells, and generated BAC-transgenic Rorc(γt)-egfpTG trans-genic mice, in which LTi cells are the only fetal cells expressing EGFP. In these mice, we visualize the cellular events that unfold during LT development, such as the migration, differentiation and activation of LTi cells, the recruitment of lymphocytes and dendritic cells to nascent LTs, and the cross-talk between hematopoietic cells and stromal cells. LTi cells are also isolated and studied both at the cellular and molecular levels.

2. Tertiary lymphoid tissues

During the first weeks of life, bacterial colonization of the murine colon and distal ileum induces the formation of numerous tLTs, termed isolated lymphoid follicles (ILFs) containing mainly B cells. We found evidence that clusters of intestinal LTi-like cells, the cryptopatches (CPs), are sensors of the colonizing bacteria. CPs differentiate into ILFs in order to increase the numbers of intestinal B cells required to maintain intestinal homeostasis. We investigate the nature of the host/commensal and host/pathogen interactions that induce the formation of ILFs, and the impact of the CP/ILF system on intestinal homeostasis. Tertiary LTs also form in chronic inflammatory lesions, as well as during lung Influenza infection. Similar to the development of secondary LTs, the formation of mature tLTs requires LTα1β2 and TNF, but the cells and chemokines involved remain to be identified. The role of pro-inflammatory Th17 cells is investigated.

3. Identifying lymphoid stromal cells initiating and supporting lymphoid tissue development

Although lymphoid stromal (LS) cells remain poorly characterized, they are critical to the process of LT formation through the expression of several structural chemokines, including CXCL13, CCL19 and CCL21, adressins, including ICAM-1 and VCAM-1, and the lymphotoxin receptor LTβR. These factors are necessary for the productive cross-talk between LTi cells and LS cells. Using an array of BAC-transgenic mice, we are visualizing LS cells and monitoring their localization, activation and differentiation during LT development, as well as their cross-talk with LTi cells. Specific LS cell populations are isolated and characterized both at the cellular and molecular levels, or ablated in vivo using conditional activation of suicide genes.

Keywords: Lymphoid tissues, inflammation, stromal cells, intestinal homeostasis, Th17 cells

Dtl.jpg

A cryptopatch (left, 400x) and an ILF (right, 100x) in mouse adult intestine. LTi cells (green), DCs (red) and B cells (blue).



  Publications

G. Eberl. 2007. From induced to programmed lymphoid tissues: the long road to pre-empt pathogens. Trends in Immunology, 28:423-428.

M.D. Boos, Y. Yokota Y, G. Eberl, and B.L. Kee. 2007. Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity. J Exp Med., 204:1119-1130.

G. Eberl. 2005. Inducible lymphoid tissues in the adult gut: recapitulation of a fetal developmental pathway? Nat. Rev. Immunol., 5:413-420.

G. Eberl, and D.R. Littman. 2004. Thymic origin of intestinal αβT cells revealed by fate mapping of RORγt+cells. Science, 305:248-251.

G. Eberl, S. Marmon, M.J. Sunshine, P.D. Rennert, Y. Choi, and D.R. Littman. 2004. An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol., 5:64-73.





Activity Reports 2007 - Institut Pasteur
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