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© The Rockefeller University Press, 0022-1007/1997/2/405/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 3, February 3, 1997 405-414

Articles

Conditions That Induce Tolerance in Mature CD4+ T Cells

Astrid Lanoue*, Constantin Bona{ddagger}, Harald von Boehmer*, and Adelaida Sarukhan*

From the * Unité Institut National de la Santé et de la Recherche Médicale 373, Institut Necker, 75730 Paris Cedex 15; and {ddagger} Department of Microbiology, Mount Sinai School of Medicine, New York 10029

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.

Address correspondence to Adelaida Sarukhan, Unité INSERM 373, Institut Necker, 156 Rue de Vaugirard, 75730 Paris Cedex 15.

This work was supported by funds from the Institut National de la Santé et de la Recherche Médicale. H. von Boehmer is supported by the Human Frontier Science Program.

1 Abbreviations used in this paper: FLUOS, fluorescein succinyl ester; HA, hemagglutinin.


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