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Full Development of Th2 Immunity Requires Both Innate and Adaptive Sources of CD154¹

Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom

The CD40-CD154 interaction is critical for Th2 response generation during helminth infection and following immunization with helminth-conditioned dendritic cells, yet the key cellular sources of these molecules have still to be defined in vivo. In this study, we demonstrate that the requirement for CD40 expression during murine Th2 response induction is restricted exclusively to the Ag-bearing dendritic cells. In contrast, development of full Th2 immunity required CD154 expression on multiple populations. In this respect, optimal production of IL-5, IL-10, and IL-13 was dependent upon CD154 expression by both CD4⁺ T cells and non-lymphoid cells. IL-4 production had less stringent costimulatory requirements, with expression of CD154 on either non-lymphoid cells or T cells alone being sufficient to enable production of this archetypal Th2 cytokine. Disparities in CD154 requirements for T cell and B cell responses were revealed during experimental schistosomiasis where, even in the face of robust Th2 generation, B cell class-switching was entirely dependent upon expression of CD154 by the lymphoid compartment. These data help define the costimulatory interactions that occur during the generation of Th2 immunity, and challenge the widely held view that CD154 expressing T cells are the sole contributors in this process.

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 Current address: Trudeau Institute, Saranac Lake, NY 12983.

³ Address correspondence and reprint requests to Dr. Andrew MacDonald, Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, EH9 3JT, U.K. E-mail address: andrew.macdonald{at}ed.ac.uk

⁴ Abbreviations used in this paper: DC, dendritic cells; BM, bone marrow; SEA, soluble egg Ag from Schistosoma mansoni; WT, wild type; LN, lymph node; Tg, transgenic.