title: CD28 costimulation is essential for human T regulatory expansion and function.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Tatiana N
authors.initials: TN
authors.lastname: Golovina
authors.forename: Tatiana
authors.initials: T
authors.lastname: Mikheeva
authors.forename: Megan M
authors.initials: MM
authors.lastname: Suhoski
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Aqui
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Tai
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Shan
authors.forename: Ronghua
authors.initials: R
authors.lastname: Liu
authors.forename: R Robert
authors.initials: RR
authors.lastname: Balcarcel
authors.forename: Nancy
authors.initials: N
authors.lastname: Fisher
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: Richard G
authors.initials: RG
authors.lastname: Carroll
authors.forename: Noel
authors.initials: N
authors.lastname: Warner
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism* / Q000502:physiology; D018929:Cell Culture Techniques; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000628:therapy; D006801:Humans; D020014:K562 Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology* / Q000637:transplantation; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D018106:CD28 Antigens