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CTLA-4 Overexpression Inhibits T Cell Responses through a CD28-B7-Dependent Mechanism¹

John J. Engelhardt^*,, Timothy J. Sullivan and James P. Allison^2,*

^* Division of Immunology, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Division of Immunology, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720

CTLA-4 has been shown to be an important negative regulator of T cell activation. To better understand its inhibitory action, we constructed CTLA-4 transgenic mice that display constitutive cell surface expression of CTLA-4 on CD4 and CD8 T cells. In both in vivo and in vitro T cell responses, CTLA-4 overexpression inhibits T cell activation. This inhibition is dependent on B7 and CD28, suggesting that overexpressed CTLA-4 inhibits responses by competing with CD28 for B7 binding or by interfering with CD28 signaling. In addition, expression of the transgene decreases the number of CD25⁺Foxp3⁺ T cells in these mice, but does not affect their suppressive ability. Our data confirm the activity of CTLA-4 as a negative regulator of T cell activation and that its action may be by multiple mechanisms.

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