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The Kidney-Renal Lymph Node-System Contributes to Cross-Tolerance against Innocuous Circulating Antigen¹

Veronika Lukacs-Kornek^*, Sven Burgdorf^*, Linda Diehl^*, Sabine Specht, Miroslaw Kornek^* and Christian Kurts^2,*

^* Institute of Molecular Medicine and Experimental Immunology and Institute of Medical Microbiology, Immunology, and Parasitology, Friedrich-Wilhelms-Universität, Bonn, Germany

Soluble Ags devoid of inflammatory stimuli, derived for example from self-serum or food proteins, induce T cell tolerance, predominantly in the spleen. In this study, we describe an additional role of the kidney-renal LN (rLN) system in tolerogenic presentation of circulating soluble Ags. Protein below albumin molecular mass constitutively passed the kidney glomerular filter and was concentrated in the tubular compartment. Enriched filterable Ag was endocytosed by kidney dendritic cells (kDCs). Simultaneously, it was transported cell independently within 2 min to DCs resident in rLNs. These DC phenotypically differed from kDCs carrying filterable Ag, and used a distinct mechanism, mannose receptor-mediated endocytosis, to internalize Ag. They activated specific CD8⁺ T cells, which subsequently proliferated without producing effector cytokines or developing cytotoxic activity, showed a curtailed lifespan and signs of apoptosis. Such T cell tolerization was independent of steady-state migratory kDC, because it occurred also when nephrectomy was performed soon after Ag injection. These findings demonstrate that the kidney dispatches concentrated blood-borne Ags to the rLNs, where they are captured by resident DCs, resulting in CD8⁺ T cell cross-tolerance. This mechanism may contribute to avoiding immunity against innocuous circulating protein Ags below albumin size.

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 the Sonderforschungsbereich 704 and by the Klinische Forschergruppe 155 of the Deutsche Forschungsgemeinschaft.

² Address correspondence and reprint requests to Dr. Christian Kurts, Institute of Molecular Medicine and Experimental Immunology, Friedrich-Wilhelms-Universität, 53105 Bonn, Germany. E-mail address: ckurts{at}web.de

³ Abbreviations used in this paper: DC, dendritic cell; LN, lymph node; rLN, renal LN; kDC, kidney DC; MHC II, MHC class II; aOVA, Alexa₆₄₇-labeled OVA; 7AAD, 7-aminoactinomycin D; cLN, cutaneous LN; MFI, mean fluorescence intensity; NX, nephrectomy; MR, mannose receptor; FSC-w, forward scatter pulse width.