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* Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, 19104;
BD Biosciences, San Jose, CA 95131;
BD Technologies, Research Triangle Park NC 27709; and
University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis, MN 55455
The costimulatory requirements required for peripheral blood T regulatory cells (Tregs) are unclear. Using cell-based artificial APCs we found that CD28 but not ICOS, OX40, 4-1BB, CD27, or CD40 ligand costimulation maintained high levels of Foxp3 expression and in vitro suppressive function. Only CD28 costimulation in the presence of rapamycin consistently generated Tregs that consistently suppressed xenogeneic graft-vs-host disease in immunodeficient mice. Restimulation of Tregs after 8–12 days of culture with CD28 costimulation in the presence of rapamycin resulted in >1000-fold expansion of Tregs in <3 wk. Next, we determined whether other costimulatory pathways could augment the replicative potential of CD28-costimulated Tregs. We observed that while OX40 costimulation augmented the proliferative capacity of CD28-costimulated Tregs, Foxp3 expression and suppressive function were diminished. These studies indicate that the costimulatory requirements for expanding Tregs differ from those for T effector cells and, furthermore, they extend findings from mouse Tregs to demonstrate that human postthymic Tregs require CD28 costimulation to expand and maintain potent suppressive function in vivo.
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1 This work was supported by Juvenile Diabetes Research Foundation Collaborative Center for Cell Therapy, a sponsored research grant from Becton, Dickinson, and Company, National Institutes of Health Grants R01CA105216, R01AI057838, R37HL56067, and P01CA670493, and a translational grant (6220) from the Leukemia and Lymphoma Society.
2 C.H.J. and J.L.R. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. James L. Riley, Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 556 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia PA 19104. E-mail address: rileyj{at}mail.med.upenn.edu
4 Abbreviations used in this paper: Treg, T regulatory cell; aAPC, artificial APC; 4-1BBL, 4-1BB ligand; CB, cord blood; CD40L, CD40 ligand; GVHD, graft-vs-host disease; NOG, NOD/scid/IL2R
cnull; OX40L, OX40 ligand.
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