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Blood, 1 October 2008, Vol. 112, No. 7, pp. 2847-2857.
Prepublished online as a Blood First Edition Paper on July 21, 2008; DOI 10.1182/blood-2008-01-132951.
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Submitted January 11, 2008
Accepted June 16, 2008
Umbilical cord blood regulatory T cell (Treg) expansion and functional effects of tumor necrosis factor receptor (TNFR) family members OX40 and 4-1BB expressed on artificial antigen-presenting Cells (aAPCs)
Keli L Hippen*, Paul Harker-Murray, Stephen B Porter, Sarah C Merkel, Aryel Londer, Dawn K Taylor, Megan Bina, Angela Panoskaltsis-Mortari, Pablo Rubinstein, Nico Van Rooijen, Tatiana N Golovina, Megan M Suhoski, Jeffrey S Miller, John E Wagner, Carl H June, James L Riley, and Bruce R Blazar
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
National Cord Blood Program, The New York Blood Center, New York City, NY, United States
Deparment of Molecular Cell Biology, Vriji Universiteit, Amsterdam, Netherlands
Abramson Family Cancer Center Research Institute, University of Pennsylvania Cancer Center, Philadelphia, PA, United States
Department of Medicine, Division of Bone Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
* Corresponding author; email: hippe002{at}umn.edu.
Previously we showed that human UCB Tregs could be expanded ~100-fold using anti-CD3/28 mAb-coated beads to provide T-cell receptor and costimulatory signals. Because Treg numbers from a single UCB unit are limited, we explored the use of cell-based aAPCs preloaded with anti-CD3/28 mAbs to achieve higher levels of Treg expansion. As compared to beads, aAPC had similar expansion properties while significantly increasing TGF- secretion and the potency of Treg suppressor function. Adding the mTOR inhibitor, rapamcycin, to bead-based cultures reduced Treg expansion without improving in vitro suppressor function. aAPCs modified to co-express OX40L or 4-1BBL expanded UCB Tregs to a significantly greater extent than bead- or non-modified aAPC cultures, reaching mean expansion levels exceeding 1250-fold. Despite the high expansion and in contrast to studies using other Treg sources, neither OX40 nor 4-1BB signaling of UCB Tregs reduced in vitro suppression. UCB Treg expanded with 4-1BBL expressing aAPC had decreased levels of pro-apoptotic bim. UCB Tregs expanded with non-modified or modified aAPCs versus beads resulted in higher survival associated with increased Treg persistence in a xenogeneic GVHD lethality model. These data offer a novel approach for UCB Treg expansion using aAPCs including those co-expressing OX40L or 4-1BBL.
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