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Cutting Edge: CD28 Controls Dominant Regulatory T Cell Activity during Active Immunization¹

Clay Lyddane^*, Beata U. Gajewska^*, Elmer Santos, Philip D. King, Glaucia C. Furtado^¶ and Michel Sadelain^*,

^* Immunology Program, Department of Radiology, and Gene Transfer and Somatic Cell Engineering Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; Immunology Program, University of Michigan, Ann Arbor, MI 48109; and ^¶ Immunobiology Center, Mount Sinai School of Medicine, New York, NY 10029

Ligation of CD28 during Ag recognition plays an important role in the generation of effective T cell responses. However, its peripheral control of regulatory T cell function remains obscure. In this study, we show that naive wild-type or CD28^–/– CD4⁺CD25^– T cells exposed to peptide in vivo develop regulatory activity that suppresses the response of adoptively transferred naive T cells to a subsequent immunogenic challenge. We find that although CD28 is engaged during the initial peptide-priming event and is essential to sustain T cell survival, it is not sufficient to prevent the dominance of regulatory T cell function. Immunization with adjuvant abrogates regulatory dominance, reducing overall Foxp3 expression in a CD28-dependent manner. We conclude that CD28 licenses active immunization by regulating Ag-induced immunoregulation.

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