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Commensal Gut Flora Drives the Expansion of Proinflammatory CD4 T Cells in the Colonic Lamina Propria under Normal and Inflammatory Conditions¹

Jan Hendrik Niess^2,*, Frank Leithäuser, Guido Adler^* and Jörg Reimann^*

^* Department of Internal Medicine I and Department of Pathology, Ulm University, Ulm, Germany

We tested in B6 mice whether the local expansion of CD4 T cells producing proinflammatory cytokines including IL-17 (Th17 cells) in the colonic lamina propria (cLP) depends on the commensal microflora. High numbers of CD4 Th17 cells were found in the lamina propria of the ileum and colon but not the duodenum, jejunum, mesenteric lymph nodes, spleen, or liver of specific pathogen-free (SPF) mice. The microflora is required for the accumulation of cytokine (IL-17, IFN-, TNF-, IL-10)-producing CD4 T cells in the cLP because only low numbers of cytokine-producing cLP CD4 T cells were found in syngeneic (age- and sex-matched) germfree mice. The fraction of cLP Th17 cells was higher in (type I and type II) IFN- but not IL-4- or IL-12p40-deficient SPF congenics. cLP CD4 Th17 cells produce IL-17 but not IFN-, TNF-, IL-4, or IL-10. cLP CD4 Th17 cells accumulate locally in colitis induced by adoptive transfer of IFN-^+/+ or IFN-^–/– CD4 T cells into congenic SPF (but not germfree) RAG^–/– hosts. In this colitis model, cLP CD4 T cells that "spontaneously" produce IL-17 progressively increase in number in the inflamed cLP, and increasing serum IL-17 levels appear as the disease progresses. Commensal bacteria-driven, local expansion of cLP CD4 Th17 cells may contribute to the pathogenesis of this inflammatory bowel disease.

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 Grants Ni 575/4-1 (to J.H.N.) and Rei 549/11-1 (to J.R.) from the Deutsche Forschungsgemeinschaft.

² Address correspondence and reprint requests to Dr. Jan Hendrik Niess, Department of Internal Medicine I, University of Ulm, Helmholtzstrasse 8/1, D-89081 Ulm, Germany. E-mail address: jan-hendrik.niess{at}uniklinik-ulm.de

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; SPF, specific pathogen free; GF, germfree; MLN, mesenteric lymph node; LP, lamina propria; cLP, colonic LP; cLPL, cLP lymphocyte; wt, wild type; NPC, nonparenchymal cell; FCM, flow cytometry; PP, Peyer’s patch; DC, dendritic cell; KO, knockout.

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