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* Department of Allergy and Rheumatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan;
Medical and Biological Laboratories, Ina, Japan; and
Department of Nutrition and Physiological Chemistry, Osaka University Medical School, Suita, Japan
Normal T cell repertoire contains regulatory T cells that control
autoimmune responses in the periphery. One recent study demonstrated
that CD4+CD25+ T cells were generated from
autoreactive T cells without negative selection. However, it is unclear
whether, in general, positive selection and negative selection of
autoreactive T cells are mutually exclusive processes in the thymus. To
investigate the ontogeny of CD4+CD25+
regulatory T cells, neo-autoantigen-bearing transgenic mice expressing
chicken egg OVA systemically in the nuclei (Ld-nOVA) were crossed with
transgenic mice expressing an OVA-specific TCR (DO11.10). Ld-nOVA
x DO11.10 mice had increased numbers of
CD4+CD25+ regulatory T cells in the thymus and
the periphery despite clonal deletion. In Ld-nOVA x DO11.10 mice,
T cells expressing endogenous TCR 
chains were
CD4+CD25- T cells, whereas T cells expressing
autoreactive TCR were selected as CD4+CD25+ T
cells, which were exclusively dominant in recombination-activating gene
2-deficient Ld-nOVA x DO11.10 mice. In contrast, in DO11.10 mice,
CD4+CD25+ T cells expressed endogenous TCR
chains, which disappeared in recombination-activating gene
2-deficient DO11.10 mice. These results indicate that part of
autoreactive T cells that have a high affinity TCR enough to cause
clonal deletion could be positively selected as
CD4+CD25+ T cells in the thymus. Furthermore,
it is suggested that endogenous TCR gene rearrangement might critically
contribute to the generation of CD4+CD25+ T
cells from nonautoreactive T cell repertoire, at least under the
limited conditions such as TCR-transgenic models, as well as the
generation of CD4+CD25- T cells from
autoreactive T cell repertoire.
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