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Ex Vivo Expansion of CD4⁺CD25⁺FoxP3⁺ T Regulatory Cells Based on Synergy between IL-2 and 4-1BB Signaling¹

Institute for Cellular Therapeutics, and Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202

Naturally occurring CD4⁺CD25⁺FoxP3⁺ T regulatory (Treg) cells require three distinct signals transduced via TCR, CD28, and IL-2R for their development and maintenance. These requirements served as the basis for several recently developed ex vivo expansion protocols that relied on the use of solid support-bound Abs to CD3 and CD28 in the presence of high dose IL-2. We report in this study that Treg cells up-regulate the expression of inducible costimulatory receptor 4-1BB in response to IL-2, and stimulation using this receptor via a novel form of 4-1BB ligand (4-1BBL) fused to a modified form of core streptavidin (SA-4-1BBL) was effective in expanding these cells up to 110-fold within 3 wk. Expanded cells up-regulated CD25, 4-1BB, and membranous TGF-β, suppressed T cell proliferation, and prevented the rejection of allogeneic islets upon adoptive transfer into graft recipients. Importantly, SA-4-1BBL rendered CD4⁺CD25^– T effector cells refractive to suppression by Treg cells. This dual function of signaling via 4-1BB, vis-à-vis Treg cell expansion and licensing T effector cells resistant to Treg cell suppression, as well as the up-regulation of 4-1BB by IL-2 may serve as important regulatory mechanisms for immune homeostasis following antigenic challenge. Stimulation using a soluble form of SA-4-1BBL represents a novel approach to expand Treg cells with potential therapeutic applications in autoimmunity and transplantation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded in parts by Grants R21 DK61333, R01 AI47864, R21 AI057903, and R21 HL080108 from the National Institutes of Health, Grant 1-2001-328 from the Juvenile Diabetes Research Foundation, Grant 1-05-JF-56 from the American Diabetes Association, and by the Commonwealth of Kentucky Research Challenge Trust Fund.

² Address correspondence and reprint requests to Dr. Haval Shirwan, Institute for Cellular Therapeutics, Donald Baxter Biomedical Building, Suite 404E, University of Louisville, 570 South Preston Street, Louisville, KY 40202. E-mail address: haval.shirwan{at}louisville.edu

³ Abbreviations used in this paper: Treg, regulatory T; Teff, effector T; DC, dendritic cell; 4-1BBL, 4-1BB ligand; SA, streptavidin; GITR, glucocorticoid-induced TNFR.