The Journal of Experimental Medicine
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Published online 23 December 2002 doi:10.1084/jem.20021429
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© Rockefeller University Press, 0022-1007/2003/1/19 $5.00
The Journal of Experimental Medicine, Volume 197, Number 1, 19-26

CD28 Costimulation Is Required for In Vivo Induction of Peripheral Tolerance in CD8 T Cells

Melanie S. Vacchio1 and Richard J. Hodes1,2

1 Experimental Immunology Branch, National Cancer Institute
2 National Institute on Aging, National Institutes of Health, Bethesda, MD 20892

Address correspondence to M.S. Vacchio, Building 10, Rm. 4B10, 10 Center Dr., Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1360. Phone: 301-435-6461; Fax: 301-496-0887; E-mail: vacchio{at}nih.gov

Whereas ligation of CD28 is known to provide a critical costimulatory signal for activation of CD4 T cells, the requirement for CD28 as a costimulatory signal during activation of CD8 cells is less well defined. Even less is known about the involvement of CD28 signals during peripheral tolerance induction in CD8 T cells. In this study, comparison of T cell responses from CD28-deficient and CD28 wild-type H-Y–specific T cell receptor transgenic mice reveals that CD8 cells can proliferate, secrete cytokines, and generate cytotoxic T lymphocytes efficiently in the absence of CD28 costimulation in vitro. Surprisingly, using pregnancy as a model to study the H-Y–specific response of maternal T cells in the presence or absence of CD28 costimulation in vivo, it was found that peripheral tolerance does not occur in CD28KO pregnants in contrast to the partial clonal deletion and hyporesponsiveness of remaining T cells observed in CD28WT pregnants. These data demonstrate for the first time that CD28 is critical for tolerance induction of CD8 T cells, contrasting markedly with CD28 independence of in vitro activation, and suggest that the role of CD28/B7 interactions in peripheral tolerance of CD8 T cells may differ significantly from that of CD4 T cells.

Key Words: pregnancy • clonal deletion • clonal anergy • B7 costimulatory molecules • cytotoxic T lymphocytes


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