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

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, Bruce R. Blazar

Research output: Contribution to journalArticle

109 Scopus citations

Abstract

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 β (TGF-β) 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 4-1 BBL 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 xenogeneic graft-versus-host disease lethality model. These data offer a novel approach for UCB Treg expansion using aAPCs, including those coexpressing OX40L or 4-1 BBL.

Original languageEnglish (US)
Pages (from-to)2847-2857
Number of pages11
JournalBlood
Volume112
Issue number7
DOIs
StatePublished - Oct 1 2008

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Hippen, K. L., Harker-Murray, P., Porter, S. B., Merkel, S. C., Londer, A., Taylor, D. K., Bina, M., Panoskaltsis-Mortari, A., Rubinstein, P., Van Rooijen, N., Golovina, T. N., Suhoski, M. M., Miller, J. S., Wagner, J. E., June, C. H., Riley, J. L., & Blazar, B. R. (2008). 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, 112(7), 2847-2857. https://doi.org/10.1182/blood-2008-01-132951