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CD8 Blockade Promotes Antigen Responsiveness to Nontolerizing Antigen in Tolerant Mice by Inhibiting Apoptosis of CD4⁺ T Cells¹

Torrey Pines Institute for Molecular Studies, San Diego, CA 92121

Using the DO11.10 CD4⁺ TCR-transgenic mouse system, we have recently shown that CD8 blockade promotes the expansion of Ag-specific regulatory CD4⁺ T cells in mice made tolerant to OVA with anti-CD4 mAb. We now show that CD8 blockade is also critical to promoting responses to nontolerizing Ag in anti-CD4 mAb-treated tolerant mice. Previously published work shows that treatment with anti-CD4 mAb without CD8 blockade induces Ag-specific tolerance. We now show that, in addition to inducing tolerance, anti-CD4 mAb treatment also significantly reduces responsiveness to irrelevant, nontolerizing Ag, and this unresponsiveness is associated with significant apoptosis of the CD4⁺ T cells. Anti-CD4 mAb-induced apoptosis is inhibited by cotreatment with anti-CD8 mAb and responsiveness to irrelevant Ag is restored, while Ag-specific tolerance is maintained. These data suggest that CD8 blockade promotes responsiveness to nontolerizing Ags in tolerant mice by inhibiting CD4⁺ T cell apoptosis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Diabetes National Research Group (DNRG0603), the Alzheimer and Aging Research Center (AARC5104), and the National Institutes of Health (DK61334) to J.D.D.

² Address correspondence and reprint requests to Dr. Joanna D. Davies, Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121. E-mail address: jdavies{at}tpims.org

³ Abbreviations used in this paper: -gal, -galactosidase; DC, dendritic cell.