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.
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.
Hippen
Keli L
KL
University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone, Blood and Marrow Transplantation, Minneapolis, USA. hippe002@umn.edu
Harker-Murray
Paul
P
Porter
Stephen B
SB
Merkel
Sarah C
SC
Londer
Aryel
A
Taylor
Dawn K
DK
Bina
Megan
M
Panoskaltsis-Mortari
Angela
A
Rubinstein
Pablo
P
Van Rooijen
Nico
N
Golovina
Tatiana N
TN
Suhoski
Megan M
MM
Miller
Jeffrey S
JS
Wagner
John E
JE
June
Carl H
CH
Riley
James L
JL
Blazar
Bruce R
BR
D053330:4-1BB Ligand / Q000378:metabolism; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology* / Q000187:drug effects; D006086:Graft vs Host Disease / Q000276:immunology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008863:Microspheres; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D053262:Receptors, OX40 / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology*
D053330:4-1BB Ligand; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D053262:Receptors, OX40; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D020123:Sirolimus