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Dendritic Cell Expression of OX40 Ligand Acts as a Costimulatory, Not Polarizing, Signal for Optimal Th2 Priming and Memory Induction In Vivo¹

Stephen J. Jenkins^*, Georgia Perona-Wright^*, Alan G. F. Worsley^*, Naoto Ishii and Andrew S. MacDonald^2,*

^* Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom; and Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan

Costimulatory cross-talk can occur at multiple cellular levels to potentiate expansion and polarization of Th responses. Although OX40L ligand (OX40L) is thought to play a key role in Th2 development, the critical cellular source of this molecule has yet to be identified. In this study, we demonstrate that OX40L expression by the initiating dendritic cell (DC) is a fundamental requirement for optimal induction of primary and memory Th2 responses in vivo. Analysis of the kinetics of the residual Th2 response primed by OX40L-deficient DC suggested a failure to stimulate appropriate expansion and/or survival of T cells, rather than an inability to polarize per se. The dependence upon OX40L was predominantly due to the provision of signaling through OX40 rather than retrograde signaling to the DC. Mechanistically, impaired Th2 priming in the absence of OX40L was not due to exaggerated regulation because there was no evidence of increased expansion or function of regulatory cell populations, suppression through IL-10 production, or hyporesponsiveness to secondary challenge. These data define a critical role for DC-derived OX40L in the induction and development of Th2 responses in vivo.

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 funded by the Wellcome Trust and the Medical Research Council U.K.

² Address correspondence and reprint requests to Dr. Andrew MacDonald, Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, U.K. E-mail address: andrew.macdonald{at}ed.ac.uk

³ Abbreviations used in this paper: DC, dendritic cell; OX40L, OX40 ligand; Treg, regulatory T cell; WT, wild type; SEA, soluble egg Ag from Schistosoma mansoni; BM, bone marrow; LN, lymph node; dLN, draining LN; MHC II, MHC class II; Foxp3, Forkhead/winged helix transcription factor 3.