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J. Exp. Med.,
Volume 188, Number 8, October 19, 1998 1493-1501
By
From the Institute of Experimental Immunology, University of Zürich, CH-8091,
Zürich, Switzerland
Activation of autoreactive T cells can lead to autoimmune diseases such as insulin-dependent
diabetes mellitus (IDDM). The initiation and maintenance of IDDM by dendritic cells (DC),
the most potent professional antigen-presenting cells, were investigated in transgenic mice expressing the lymphocytic choriomeningitis virus glycoprotein (LCMV-GP) under the control
of the rat insulin promoter (RIP-GP mice). We show that after adoptive transfer of DC constitutively expressing the immunodominant cytotoxic T lymphocyte (CTL) epitope of the
LCMV-GP, RIP-GP mice developed autoimmune diabetes. Kinetic and functional studies of
DC-activated CTL revealed that development of IDDM was dependent on dose and timing of
antigenic stimulation. Strikingly, repeated CTL activation by DC led to severe destructive
mononuclear infiltration of the pancreatic islets but also to de novo formation of islet-associated organized lymphoid structures in the pancreatic parenchyma. In addition, repetitive DC
immunization induced IDDM with lymphoid neogenesis also in perforin-deficient RIP-GP
mice, illustrating that CD8+ T cell-dependent inflammatory mechanisms independent of perforin could induce IDDM. Thus, DC presenting self-antigens not only are potent inducers of
autoreactive T cells, but also help to maintain a peripheral immune response locally; therefore,
the induction of autoimmunity against previously ignored autoantigens represents a potential
hazard, particularly in DC-based antitumor therapies.
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