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

作者：Hippen Keli L^*; Harker Murray Paul; Porter Stephen B; Merkel Sarah C; Londer Aryel; Taylor Dawn K; Bina Megan; Panoskaltsis Mortari Angela; Rubinstein Pablo; Van Rooijen Nico; Golovina Tatiana N; Suhoski Megan M; Miller Jeffrey S; Wagner John E; June Carl H; Riley James L; Blazar Bruce R

来源：Blood, 2008, 112(7): 2847-2857.

DOI：10.1182/blood-2008-01-132951

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 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 Tregs expanded with 4-1BBL expressing aAPCs had decreased levels of proapoptotic bim. UCB Tregs expanded with non-modified 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 4-1BBL.

• 出版日期2008-10-1