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Lymph Node Stromal Cells Support Dendritic Cell-Induced Gut-Homing of T Cells¹

Rosalie Molenaar,^* Mascha Greuter,^2* Arnold P. J. van der Marel,^2* Ramon Roozendaal,^* Stefan F. Martin, Fanny Edele, Jochen Huehn, Reinhold Förster, Tom O'Toole,^* Wendy Jansen,^* Inge L. Eestermans,^* Georg Kraal,^* and Reina E. Mebius^3*

^*Department of Molecular Cell Biology and Immunology, VU (Vrije Universiteit) University Medical Center, Amsterdam, The Netherlands; Allergy Research Group, Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany; Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany; and Institute of immunology, Hannover Medical School, Hannover, Germany

T cells are imprinted to express tissue-specific homing receptors upon activation in tissue-draining lymph nodes, resulting in their migration to the site of Ag entry. Expression of gut-homing molecules ₄β₇ and CCR9 is induced by retinoic acid, a vitamin A metabolite produced by retinal dehydrogenases, which are specifically expressed in dendritic cells as well as stromal cells in mucosa-draining lymph nodes. In this study, we demonstrate that mesenteric lymph node stromal cell-derived retinoic acid can directly induce the expression of gut-homing molecules on proliferating T cells, a process strongly enhanced by bone marrow-derived dendritic cells in vitro. Therefore, cooperation of sessile lymph node stromal cells with mobile dendritic cells warrants the imprinting of tissue specific homing receptors on activated T cells.

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 a VICI Grant (918.56.612) from the Netherlands Organization for Scientific Research (to R.M., M.J.G., R.R., and R.E.M.) and Deutsche Forschungsgemeinschaft, DFG Grants MA1567/8-1 (to S.F.M. and F.E.) and SFB621-A1 (to R.F.).

² M.G. and A.P.J.v.d.M. contributed equally to this work.

³ Address correspondence and reprint requests to Reina E. Mebius, Department of Molecular Cell Biology and Immunology, VU (Vrije Universiteit) University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail address: r.mebius{at}vumc.nl

⁴ Abbreviations used in this paper: DC, dendritic cell; RA, retinoic acid; RALDH, retinal dehydrogenase; LN, lymph node; PLN, peripheral lymph node; MLN, mesenteric lymph node; BM-DC, bone marrow-derived DC; FRC, fibroblastic reticular cell; tMLN, transplanted MLN; tPLN, transplanted PLN; PNAd, peripheral lymph node addressin.