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Division of Molecular Pathogenesis, Skirball Institute of Biomolecular Medicine, and Department of Pathology, and
Sackler Institute of Graduate Biomedical Sciences, New York University Medical Center, New York, NY 10016
Spontaneous experimental autoimmune encephalomyelitis arises in
100% of mice exclusively harboring myelin basic protein-specific T
cells, and can be prevented by a single injection of CD4+ T
cells obtained from normal donors. Given the powerful regulatory effect
of the transferred T cells, we further investigated their properties,
and, in particular, their repertoire requirements. Transfer of
monoclonal OVA-specific CD4+ T cells did not confer
protection from disease even when present at very high proportions
(about 80% of total lymphocytes). Lack of protection was also evident
after immunization of these animals with OVA, indicating that not just
any postthymic CD4+ T cells has the potential to become
regulatory. However, protection was conferred by cells bearing limited
TCR diversity, including cells expressing a single V
4 TCR chain or
cells lacking N nucleotides. We also investigated whether coexpression
of the myelin basic protein-specific TCR with another TCR in a single
cell would alter either pathogenesis or regulation. This was not the
case, as myelin basic protein-specific/OVA-specific recombinase
activating gene-1-/- double TCR transgenic mice still
developed experimental autoimmune encephalomyelitis spontaneously even
after immunization with OVA. Based on this evidence, we conclude that
CD4+ T regulatory cells do not express canonical TCRs and
that the altered signaling properties brought about by coexpression of
two TCRs are not sufficient for the generation of regulatory T cells.
Instead, our results indicate that regulatory T cells belong to a
population displaying wide TCR diversity, but in which TCR specificity
is central to their protective function.
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