The Journal of Experimental Medicine
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Published online 17 September 2001. doi:10.1084/jem.194.6.769
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© The Rockefeller University Press, 0022-1007/2001/9/769/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 6, September 17, 2001 769-780

Original Article

Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo

Daniel Hawigera, Kayo Inabac,e, Yair Dorsetta, Ming Guoa, Karsten Mahnkec, Miguel Riverac, Jeffrey V. Ravetchd, Ralph M. Steinmanc, and Michel C. Nussenzweiga,b

a Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10021
b Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021
c Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021
d Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021
e Laboratory of Immunobiology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan
Department of Molecular Immunology/HHMI, RRB Rm. 470, Box 220, 1230 York Ave., New York, NY 10021.212-327-8370212-327-8067

nussen{at}mail.rockefeller.edu

Dendritic cells (DCs) have the capacity to initiate immune responses, but it has been postulated that they may also be involved in inducing peripheral tolerance. To examine the function of DCs in the steady state we devised an antigen delivery system targeting these specialized antigen presenting cells in vivo using a monoclonal antibody to a DC-restricted endocytic receptor, DEC-205. Our experiments show that this route of antigen delivery to DCs is several orders of magnitude more efficient than free peptide in complete Freund's adjuvant (CFA) in inducing T cell activation and cell division. However, T cells activated by antigen delivered to DCs are not polarized to produce T helper type 1 cytokine interferon {gamma} and the activation response is not sustained. Within 7 d the number of antigen-specific T cells is severely reduced, and the residual T cells become unresponsive to systemic challenge with antigen in CFA. Coinjection of the DC-targeted antigen and anti-CD40 agonistic antibody changes the outcome from tolerance to prolonged T cell activation and immunity. We conclude that in the absence of additional stimuli DCs induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness.

Key Words: antigen delivery • DEC 205 • dendritic cells • peripheral T cell tolerance • CD40

Abbreviations used in this paper: CFSE, 5-(6)-carboxyfluorescein diacetate succinimidyl diester; DC, dendritic cell; HEL, hen egg lysozyme; MMR, macrophage mannose receptor.

© 2001 The Rockefeller University Press


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