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Inflammation Recapitulates the Ontogeny of Lymphoid Stromal Cells¹

Lucie Peduto^*, Sophie Dulauroy^*, Matthias Lochner^*, Gerald F. Späth, Miguel A. Morales, Ana Cumano and Gérard Eberl^2,*

^* Laboratory of Lymphoid Tissue Development, Institut Pasteur, Centre National de la Recherche Scientifique, Unité de Recherche Associée 1961, Paris, France; Laboratoire de Virulence Parasitaire, Institut Pasteur, Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Institut National de la Santé et de la Recherche Médicale Avenir, Paris, France; and Unité du Développement des Lymphocytes, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale U668, Paris, France

Stromal cells in lymphoid tissues regulate lymphocyte recruitment and survival through the expression of specific chemokines and cytokines. During inflammation, the same signals recruit lymphocytes to the site of injury; however, the "lymphoid" stromal (LS) cells producing these signals remain poorly characterized. We find that mouse inflammatory lesions and tumors develop gp38⁺ LS cells, in recapitulation of the development of LS cells early during the ontogeny of lymphoid organs and the intestine, and express a set of genes that promotes the development of lymphocyte-permissive tissues. These gp38⁺ LS cells are induced by a robust pathway that requires myeloid cells but not known Toll- or NOD-like receptors, the inflammasome, or adaptive immunity. Parabiosis and inducible genetic cell fate mapping experiments indicate that local precursors, presumably resident fibroblasts rather that circulating precursors, massively proliferate and give rise to LS cells during inflammation. Our results show that LS cells are both programmed during ontogeny and reinduced during inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Institut Pasteur, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Agence Nationale de la Recherche, Fondation de la Recherche Médicale, Mairie de Paris and a Marie Curie Excellence grant.

L.P. designed and performed all experiments and wrote the paper; S.D. performed qRT-PCR; M.L. performed FACS sorting; G.F.S. and M.A.M. provided Leishmania-infected mice; A.C. performed FACS sorting; G.E. designed and directed the study and wrote the paper; and all authors critically reviewed the manuscript.

² Address correspondence and reprint requests to Dr. Gérard Eberl, Laboratory of Lymphoid Tissue Development, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris, France. E-mail address: gerard.eberl{at}pasteur.fr

³ Abbreviations used in this paper: LS cell, lymphoid stromal cell; LN, lymph node; PP, Peyer’s patch; FDC, follicular dendritic cell; FRC, fibroblastic reticular cell; DC, dendritic cell; SMA, smooth muscle actin; LT₁β₂, lymphotoxin ₁β₂; tLT, tertiary lymphoid tissue; EMT, epithelial to mesenchymal transition; BAC, bacterial artificial chromosome; EGFP, enhanced GFP; LTβR, lymphotoxin-β receptor; LEC, lymphatic endothelial cell; LTi cell, lymphoid tissue inducer cell; NLR, Nod-like receptor.

⁴ The online version of this article contains supplemental material.