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Regulated Compartmentalization of Programmed Cell Death-1 Discriminates CD4⁺CD25⁺ Resting Regulatory T Cells from Activated T Cells¹

Giorgio Raimondi^*, William J. Shufesky^*, Daisuke Tokita^*, Adrian E. Morelli^* and Angus W. Thomson^2,*,

^* Thomas E. Starzl Transplantation Institute and Department of Surgery and Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213

More effective discrimination between CD4⁺CD25⁺ regulatory T cells (Treg) and activated T cells would significantly improve the current level of purification of Treg and their therapeutic application. We observed that 90% of Treg (positive for the nuclear transcription factor Forkhead winged helix protein-3 and able to inhibit naive T cell proliferation) isolated from the spleens or lymph nodes of normal mice did not express significant levels of the inhibitory receptor programmed cell death-1 (PD-1) on their surface, but retained PD-1 intracellularly. An identical phenotype was also identified for human CD4⁺CD25^high T cells isolated from peripheral blood of healthy volunteers. By contrast, activated T cells expressed high levels of surface PD-1 that paralleled up-regulation of CD25 during effector cell expansion. This distinction allowed us to isolate CD4⁺CD25⁺PD-1^– T cells with suppressive activity from mice immunized with mature allogeneic dendritic cells. Although purification was limited to resting Treg because TCR ligation induced up-regulation of surface PD-1, this strategy nevertheless represents a valuable step toward more definitive characterization of Treg and their improved purification for therapeutic assessment.

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