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Cellular Immunology Laboratory, Institut National de la Santé et de la Recherche Médicale, CJF 9711, Hôpital Pitié-Salpêtrière, Paris, France;
Unité de Biologie Moleculaire du Gène, Institut National de la Santé et de la Recherche Médicale, Unité 277, Institut Pasteur, Paris, France; and
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7627, Hôpital Pitié-Salpêtrière, Paris, France
CD8+ T cells are important effectors, as well as
regulators, of organ-specific autoimmunity. Compared with Tc1-type
CD8+ cells, Tc2 cells have impaired anti-viral and
anti-tumor effector functions, although no data are yet available
on their pathogenic role in autoimmunity. Our aim was to explore the
role of autoreactive Tc1 and Tc2 cells in autoimmune diabetes. We set
up an adoptive transfer model in which the recipients were transgenic
mice expressing influenza virus hemagglutinin (HA) specifically in
their pancreatic 
islet cells (rat insulin promoter-HA mice) and
islet-specific Tc1 and Tc2 cells were generated in vitro from
HA-specific CD8+ cells of TCR transgenic mice (CL4-TCR
mice). One million Tc1 cells, differentiated in vitro in the presence
of IL-12, transferred diabetes in 100% of nonirradiated adult rat
insulin promoter-HA recipients; the 50% diabetogenic dose was 5
x 105. Highly polarized Tc2 cells generated in the
presence of IL-4, IL-10, and anti-IFN-
mAb had a relatively low,
but definite, diabetogenic potential. Thus, 5 x 106
Tc2 cells caused diabetes in 6 of 18 recipients, while the same dose of
naive CD8+ cells did not cause diabetes. Looking for the
cause of the different diabetogenic potential of Tc1 and Tc2 cells, we
found that Tc2 cells are at least as cytotoxic as Tc1 cells but their
accumulation in the pancreas is slower, a possible consequence of
differential chemokine receptor expression. The diabetogenicity of
autoreactive Tc2 cells, most likely caused by their cytotoxic activity,
precludes their therapeutic use as regulators of
autoimmunity.
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