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*
Department of Microbiology and Immunology and the Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA 90095;
Department of Medicine and Microbiology Immunology and Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA 93143; and
Department of Immunology, Department of Cellular and Molecular Biology, Lund University, Lund, Sweden
Humans and mice contain significant populations of T cells that are
reactive for autologous CD1 molecules. Using a panel of five mouse CD1
(mCD1)-autoreactive T cell hybridomas, we show here that this
autoreactivity does not correlate with the level of CD1 expression. In
some cases, these autoreactive T cells can distinguish between
different cell types that express the same CD1 molecule, suggesting
that some factor in addition to CD1 expression is critical for
autoreactive T cell stimulation. To determine whether a CD1-bound
ligand may be required, we expressed mutant mCD1 molecules that are
defective for the putative endosomal localization sequence in the
cytoplasmic domain. We demonstrate that mCD1, like its human CD1
homologues, is found in endosomes, and that it colocalizes extensively
with the DM molecule. We further demonstrate, by site-directed
mutagenesis, that the tyrosine in the cytoplasmic sequence is required
for this endosomal localization. A T cell hybrid expressing Vß8 and
V
14, the major TCR expressed by NK1+ T cells,
exhibited greatly diminished reactivity to mutant CD1 molecules that do
not traffic through endosomes, although the reactivity of other T cell
hybrids to this mutant was not greatly affected. Therefore, we propose
that at least some of the autoreactive T cells require endosomally
derived CD1-bound ligands, and that they are capable of distinguishing
between a diverse set of such self-ligands, which might be either
autologous lipoglycans or peptides.
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