CD28 costimulation is essential for human T regulatory expansion and function.
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.
Golovina
Tatiana N
TN
Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Mikheeva
Tatiana
T
Suhoski
Megan M
MM
Aqui
Nicole A
NA
Tai
Victoria C
VC
Shan
Xiaochuan
X
Liu
Ronghua
R
Balcarcel
R Robert
RR
Fisher
Nancy
N
Levine
Bruce L
BL
Carroll
Richard G
RG
Warner
Noel
N
Blazar
Bruce R
BR
June
Carl H
CH
Riley
James L
JL
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
D018106:CD28 Antigens