The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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Published online 14 June 2004 doi:10.1084/jem.20040317
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 12, 1607-1618
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The Linkage of Innate to Adaptive Immunity via Maturing Dendritic Cells In Vivo Requires CD40 Ligation in Addition to Antigen Presentation and CD80/86 Costimulation

Shin-ichiro Fujii, Kang Liu, Caroline Smith, Anthony J. Bonito, and Ralph M. Steinman

Laboratory of Cellular Physiology and Immunology and the Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021

Address correspondence to R.M. Steinman, Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021. Phone: (212) 327-8106; Fax: (212) 327-8875; email: steinma{at}mail.rockefeller.edu

Dendritic cell (DC) maturation is an innate response that leads to adaptive immunity to coadministered proteins. To begin to identify underlying mechanisms in intact lymphoid tissues, we studied {alpha}-galactosylceramide. This glycolipid activates innate V{alpha}14+ natural killer T cell (NKT) lymphocytes, which drive DC maturation and T cell responses to ovalbumin antigen. Hours after giving glycolipid i.v., tumor necrosis factor (TNF)–{alpha} and interferon (IFN)-{gamma} were released primarily by DCs. These cytokines induced rapid surface remodeling of DCs, including increased CD80/86 costimulatory molecules. Surprisingly, DCs from CD40–/– and CD40L–/– mice did not elicit CD4+ and CD8+ T cell immunity, even though the DCs exhibited presented ovalbumin on major histocompatibility complex class I and II products and expressed high levels of CD80/86. Likewise, an injection of TNF-{alpha} up-regulated CD80/86 on DCs, but CD40 was required for immunity. CD40 was needed for DC interleukin (IL)-12 production, but IL-12p40–/– mice generated normal ovalbumin-specific responses. Therefore, the link between innate and adaptive immunity via splenic DCs and innate NKT cells has several components under distinct controls: antigen presentation in the steady state, increases in costimulatory molecules dependent on inflammatory cytokines, and a distinct CD40/CD40L signal that functions together with antigen presentation ("signal one") and costimulation ("signal two") to generate functioning CD4+ T helper cell 1 and CD8+ cytolytic T lymphocytes.

Key Words: {alpha}-galactosylceramide • maturation • CD40 • NKT • TNF-{alpha}

The online version of this article contains supplemental material.

Abbreviations used in this paper: {alpha}-GalCer, {alpha}-galactosylceramide; CFSE, carboxyfluorescein succinimidyl ester; MLR, mixed leukocyte reaction.


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