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Regulatory CD4(+) T cells are known to develop during the induction of donor-specific peripheral tolerance to transplanted tissues; it is proposed that such tolerance is a consequence of persistent, danger-free stimulation by Ag. To test this hypothesis, male RAG-1(-/-) mice were recolonized with small numbers of monospecific CD4(+) T cells specific for the male H-2E(k)-restricted Ag Dby. After 6 wk in the male environment, the monospecific CD4(+) T cells, having recolonized the host, had become anergic to stimulation in vitro and had acquired a regulatory capacity. CD4(+) T cells in these mice expressed higher levels of CTLA-4 and glucocorticoid-induced TNF-related receptor than naive CD4(+) T cells, but only 3% of the recolonizing cells were CD25(+) and did not express significant foxP3 mRNA. In vivo, these tolerant T cells could censor accumulation of, and IFN-gamma production by, naive T cells, with only a slight inhibition of proliferation. This suppressive effect was not reversed by the addition of fresh bone marrow-derived male dendritic cells. These results suggest that persistent exposure to Ag in conditions that fail to evoke proinflammatory stimuli leads to the development of T cells that are both anergic and regulatory.

Original publication




Journal article


J Immunol

Publication Date





5900 - 5907


Adoptive Transfer, Amino Acid Sequence, Animals, Antigens, CD4-Positive T-Lymphocytes, Cell Differentiation, Cell Division, Clonal Anergy, Coculture Techniques, DEAD-box RNA Helicases, Female, Graft vs Host Disease, Homeodomain Proteins, Immunophenotyping, Interphase, Male, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Knockout, Mice, Transgenic, Minor Histocompatibility Antigens, Molecular Sequence Data, Proteins, RNA, Messenger, Spleen, T-Lymphocyte Subsets