CONDITIONS THAT INDUCE TOLERANCE IN MATURE CD4(-CELLS() T)

Establishment of antigen-specific tolerance among mature T cells has b een a long debated, yet poorly understood issue. In this study we have used transgenic mice bearing a class II-restricted TCR specific for t he hemmagglutinin of the influenza virus in order to test the behavior of CD4(+) T cells upon exposure to antigen in different forms and dos es. We first studied the fate of T cells expressing the transgenic TCR (6.5) in double transgenic mice where HA was expressed as a self anti gen by hemapoietic cells. In these mice, we found some mature T cells in periphery that had escaped thymic deletion and that showed signs of activation but which were anergic. Mature CD4(+)6.5(+) cells that wer e transferred into antigen-containing recipients went through an initi al phase of expansion after which most cells were deleted and those re maining became unresponsive, as previously described for CD8(+) cells. Inducing tolerance in CD4(+)6.5(+) cells in situ in single transgenic mice proved a difficult task: classical protocols using single doses of soluble or deaggregated antigen as well as feeding antigen all fail ed to induce antigen-specific unresponsiveness. It was only after decr easing cell numbers by CD4 antibody treatment and by repeatedly reintr oducing antigen thereafter that unresponsiveness of 6.5(+) cells was a chieved and maintained. In no case could we observe the appearance of antigen-specific T cells with a Th2 cytokine profile among the remaini ng cells and therefore conclude that deletion and anergy represent the major mechanisms of tolerance in our studies.