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IL-12 Instructs Skin Homing of Human Th2 Cells¹

Tilo Biedermann^2,*,, Günther Lametschwandtner^*, Kirsten Tangemann^*, Julia Kund^*, Sonja Hinteregger^*, Nicole Carballido-Perrig^*, Antal Rot^*, Christoph Schwärzler^* and José M. Carballido^2,*

^* Novartis Institutes for Biomedical Research, Vienna, Austria; and Department of Dermatology, Eberhard-Karls-University, Tüebingen, Germany

Distinct pattern of homing receptors determines the tissue preference for T cells to exert their effector functions. This homing competence is mostly determined early during T cell activation of naive T cells. In contrast, mechanisms governing the acquisition of particular homing receptors by T cells of the memory phenotype remain enigmatic. Th2 cell-mediated allergic diseases tend to flare during infections despite that these infections prime APCs to produce the prototypic Th1 cell-differentiating cytokine IL-12. In this study, we investigate the effect of IL-12 on the regulation of cutaneous lymphocyte Ag (CLA) on differentiated Th2 cells and consequences of this expression for allergic inflammation. Upon activation with IL-12, CLA^– Th2 cells rapidly up-regulated IL-12R2 chain, (1-3)-fucosyltransferase VII, and CLA molecules. IL-12-mediated CLA expression on Th2 cells was functional because it mediated rolling of these Th2 cells on E-selectin in vitro and migration into human skin grafts in SCID mice. CLA induction occurred immediately after exposure to IL-12 and was independent of IFN- expression. In accordance, the transcription factor mediating IFN- expression, T-bet, does not directly affect CLA expression. However, CLA expression was further enhanced after IL-12 treatment of T-bet⁺-transfected Th2 cells in agreement with an increased IL-12 responsiveness of these cells caused by T-bet. The finding that IL-12 conferred skin-homing potential to already differentiated Th2 cells before inducing a switch in their cytokine production profile may explain the observed exacerbation of allergic skin diseases following bacterial infections.

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 partially supported by grants from the Deutsche Forschungsgemeinschaft (DFG Bi 696/3-1; SFB 685 A6), Landesstiftung Baden-Württemberg (P-LS-AL/17), and the medical faculty, University of Tübingen (F126810) (to T.B.).

² Address correspondence and reprint requests to Dr. Tilo Biedermann, Department of Dermatology, Eberhard-Karls-University, Liebermeisterstrasse 25, 72076 Tuebingen, Germany; E-mail address: tilo.biedermann{at}med.uni-tuebingen.de or Dr. José M. Carballido, Novartis Institutes for Biomedical Research, Brunnerstrasse 59, 1235 Vienna, Austria; E-mail address: jose.carballido{at}novartis.com

³ Abbreviations used in this paper: DC, dendritic cell; AD, atopic dermatitis; AM, acetoxymethyl; CLA, cutaneous lymphocyte Ag; FucTVII, fucosyltransferase VII; HPRT, hypoxanthine phosphoribosyltransferase; pTh2, Th2 cells from PBMC.