Blockade of Programmed Death-1 in Young (New Zealand Black × New Zealand White)F1 Mice Promotes the Suppressive Capacity of CD4+ Regulatory T Cells Protecting from Lupus-like Disease

Abstract

Programmed death-1 (PD-1) usually acts as a negative signal for T cell activation, and its expression on CD8+Foxp3+ T cells is required for their suppressive capacity. In this study, we show that PD-1 signaling is required for the maintenance of functional regulatory CD4+CD25+Foxp3+ regulatory T cells (CD4+ Treg) that can control autoimmunity in (New Zealand Black × New Zealand White)F1 lupus mice. PD-1 signaling induced resistance to apoptosis and prolonged the survival of CD4+ Treg. In vivo, the blockade of PD-1 with a neutralizing Ab reduced PD-1 expression on CD4+ Treg (PD1loCD4+ Treg). PD1loCD4+ Treg had an increased ability to promote B cell apoptosis and to suppress CD4+ Th as compared with CD4+ Treg with elevated PD-1 expression (PD1hiCD4+ Treg). When PD-1 expression on CD4+ Treg was blocked in vitro, PD1loCD4+ Treg suppressed B cell production of IgG and anti-dsDNA Ab. Finally, in vitro studies showed that the suppressive capacity of CD4+ Treg depended on PD-1 expression and that a fine-tuning of the expression of this molecule directly affected cell survival and immune suppression. These results indicate that PD-1 expression has multiple effects on different immune cells that directly contribute to a modulation of autoimmune responses.