Umbilical cord blood regulatory T-cell expansion and functional effects of tumor necrosis factor receptor family members OX40 and 4-1BB expressed on artificial antigen-presenting cells. Blood 2008 Oct 01;112(7):2847-57
Date
07/23/2008Pubmed ID
18645038Pubmed Central ID
PMC2556620DOI
10.1182/blood-2008-01-132951Scopus ID
2-s2.0-53449091065 (requires institutional sign-in at Scopus site) 128 CitationsAbstract
Previously, we showed that human umbilical cord blood (UCB) regulatory T cells (Tregs) could be expanded approximately 100-fold using anti-CD3/28 monoclonal antibody (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 artificial antigen-presenting cells (aAPCs) preloaded with anti-CD3/28 mAbs to achieve higher levels of Treg expansion. Compared with beads, aAPCs had similar expansion properties while significantly increasing transforming growth factor beta (TGF-beta) secretion and the potency of Treg suppressor function. aAPCs modified to coexpress OX40L or 4-1BBL expanded UCB Tregs to a significantly greater extent than bead- or nonmodified 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 Tregs expanded with 4-1BBL expressing aAPCs had decreased levels of proapoptotic bim. UCB Tregs expanded with nonmodified or modified aAPCs versus beads resulted in higher survival associated with increased Treg persistence in a xeno-geneic graft-versus-host disease lethality model. These data offer a novel approach for UCB Treg expansion using aAPCs, including those coexpressing OX40L or 4-1BBL.
Author List
Hippen KL, Harker-Murray P, Porter SB, Merkel SC, Londer A, Taylor DK, Bina M, Panoskaltsis-Mortari A, Rubinstein P, Van Rooijen N, Golovina TN, Suhoski MM, Miller JS, Wagner JE, June CH, Riley JL, Blazar BRAuthor
Paul D. Harker-Murray MD, PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
4-1BB LigandAnimals
Antigen-Presenting Cells
Apoptosis Regulatory Proteins
Bcl-2-Like Protein 11
Cell Proliferation
Cell Survival
Cells, Cultured
Fetal Blood
Graft vs Host Disease
Humans
Membrane Proteins
Mice
Microspheres
Proto-Oncogene Proteins
Receptors, OX40
Sirolimus
Survival Analysis
T-Lymphocytes, Regulatory
Tumor Necrosis Factor Receptor Superfamily, Member 9