Generation of Anergic and Regulatory T Cells following Prolonged Exposure to a Harmless Antigen

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Abstract
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-2Ek-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-γ 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.

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