A novel alloantigen-specific CD8+PD1+ regulatory T cell induced by ICOS-B7h blockade in vivo.
Delayed ICOS-B7h signal blockade promotes significant prolongation of cardiac allograft survival in wild-type but not in CD8-deficient C57BL/6 recipients of fully MHC-mismatched BALB/c heart allografts, suggesting the possible generation of CD8(+) regulatory T cells in vivo. We now show that the administration of a blocking anti-ICOS mAb results in the generation of regulatory CD8(+) T cells. These cells can transfer protection and prolong the survival of donor-specific BALB/c, but not third party C3H, heart grafts in CD8-deficient C57BL/6 recipients. This is unique to ICOS-B7h blockade, because B7 blockade by CTLA4-Ig prolongs graft survival in CD8-deficient mice and does not result in the generation of regulatory CD8(+) T cells. Those cells localize to the graft, produce both IFN-gamma and IL-4 after allostimulation in vitro, prohibit the expansion of alloreactive CD4(+) T cells, and appear to mediate a Th2 switch of recipient CD4(+) T cells after adoptive transfer in vivo. Finally, these cells are not confined to the CD28-negative population but express programmed death 1, a molecule required for their regulatory function in vivo. CD8(+)PD1(+) T cells suppress alloreactive CD4(+) T cells but do not inhibit the functions by alloreactive CD8(+) T cells in vitro. These results describe a novel allospecific regulatory CD8(+)PD1(+) T cell induced by ICOS-B7h blockade in vivo.
Izawa
Atsushi
A
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Yamaura
Kazuhiro
K
Albin
Monica J
MJ
Jurewicz
Mollie
M
Tanaka
Katsunori
K
Clarkson
Michael R
MR
Ueno
Takuya
T
Habicht
Antje
A
Freeman
Gordon J
GJ
Yagita
Hideo
H
Abdi
Reza
R
Pearson
Todd
T
Greiner
Dale L
DL
Sayegh
Mohamed H
MH
Najafian
Nader
N
D019264:Adoptive Transfer; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D060945:Inducible T-Cell Co-Stimulator Ligand; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D011506:Proteins / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D007519:Isoantigens; D011506:Proteins