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From the * Unité Institut National de la Santé et de la Recherche Médicale 373, Institut Necker,
75730 Paris Cedex 15; and Establishment of antigen-specific tolerance among mature T cells has been a long debated, yet
poorly understood issue. In this study we have used transgenic mice bearing a class II-restricted TCR specific for the hemmagglutinin of the influenza virus in order to test the behavior of
CD4+ T cells upon exposure to antigen in different forms and doses. 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 antigen 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 were transferred into antigen-containing recipients went
through an initial phase of expansion after which most cells were deleted and those remaining
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 failed to induce antigen-specific unresponsiveness. It was only after decreasing cell numbers by CD4 antibody treatment and by
repeatedly reintroducing antigen thereafter that unresponsiveness of 6.5+ cells was achieved
and maintained. In no case could we observe the appearance of antigen-specific T cells with a
Th2 cytokine profile among the remaining cells and therefore conclude that deletion and anergy represent the major mechanisms of tolerance in our studies.
Department of Microbiology, Mount Sinai School of Medicine, New
York 10029
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