Cell cycle block in anergic T cells during tolerance induction.

The induction of anergy, or T cell unresponsiveness to antigen, is preceded by T cell activation and cell division in response to fed antigens. These events parallel the activation observed in T cells following sensitization with antigen and adjuvant. The events that distinguish eventual sensitization versus tolerance remain unclear. Using a T lymphocyte transfer model specific to OVA, we demonstrated previously that oral encounter with antigen leads to functional anergy. Antigen-specific CD4+ T cells nevertheless become activated and cycle briefly after encounter with antigen. In this study, we measured the extent of cell cycling of antigen-specific T cells after oral encounter with their antigen. Whereas T cells cycle on the average of eight times in 4 days after conventional immunization, an abortive proliferation was observed in the draining LN T cells after oral encounter with antigen; OVA-specific T cells divided fewer times after exposure to fed OVA, compared to T cells in mice immunized with OVA. This abortive proliferation is antigen specific and not due to bystander suppression, as coadministration of an unrelated antigen that was previously used as a tolerogen does not alter the degree of abortive proliferation. Measurement of BrdU incorporation in mice that were previously fed ovalbumin indicates that up to 3 days following feeding, OVA-specific cells are actively cycling in vivo. However, by day 4, they have stopped cycling while identical T cells in OVA-sensitized mice continue to cycle. Our results indicate either that tolerance is a default pathway and a secondary stimulus is required at day 3 to progress to sensitization, or that elements that limit cell cycle progression are provided for tolerance induction.