CD28 costimulation is essential for human T regulatory expansion and function

Tatiana N. Golovina, Tatiana Mikheeva, Megan M. Suhoski, Nicole A. Aqui, Victoria C. Tai, Xiaochuan Shan, Ronghua Liu, R. Robert Balcarcel, Nancy Fisher, Bruce L. Levine, Richard G. Carroll, Noel Warner, Bruce R. Blazar, Carl H. June, James L. Riley

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

Abstract

The costimulatory requirements required for peripheral blood T regulatory cells (Tregs) are unclear. Using cell-based artificial APCs we found that CD28 but not ICOS, OX40, 4-1BB, CD27, or CD40 ligand costimulation maintained high levels of Foxp3 expression and in vitro suppressive function. Only CD28 costimulation in the presence of rapamycin consistently generated Tregs that consistently suppressed xenogeneic graft-vs-host disease in immunodeficient mice. Restimulation of Tregs after 8-12 days of culture with CD28 costimulation in the presence of rapamycin resulted in >1000-fold expansion of Tregs in <3 wk. Next, we determined whether other costimulatory pathways could augment the replicative potential of CD28-costimulated Tregs. We observed that while OX40 costimulation augmented the proliferative capacity of CD28-costimulated Tregs, Foxp3 expression and suppressive function were diminished. These studies indicate that the costimulatory requirements for expanding Tregs differ from those for T effector cells and, furthermore, they extend findings from mouse Tregs to demonstrate that human postthymic Tregs require CD28 costimulation to expand and maintain potent suppressive function in vivo.

Original languageEnglish (US)
Pages (from-to)2855-2868
Number of pages14
JournalJournal of Immunology
Volume181
Issue number4
DOIs
StatePublished - Aug 15 2008

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