CD70 signaling is critical for CD28-independent CD8+ T cell-mediated alloimmune responses in vivo.
The inability to reproducibly induce robust and durable transplant tolerance using CD28-B7 pathway blockade is in part related to the persistence of alloreactive effector/memory CD8(+) T cells that are less dependent on this pathway for their cellular activation. We studied the role of the novel T cell costimulatory pathway, CD27-CD70, in alloimmunity in the presence and absence of CD28-B7 signaling. CD70 blockade prolonged survival of fully mismatched vascularized cardiac allografts in wild-type murine recipients, and in CD28-deficient mice induced long-term survival while significantly preventing the development of chronic allograft vasculopathy. CD70 blockade had little effect on CD4(+) T cell function but prevented CD8(+) T cell-mediated rejection, inhibited the proliferation and activation of effector CD8(+) T cells, and diminished the expansion of effector and memory CD8(+) T cells in vivo. Thus, the CD27-CD70 pathway is critical for CD28-independent effector/memory CD8(+) alloreactive T cell activation in vivo. These novel findings have important implications for the development of transplantation tolerance-inducing strategies in primates and humans, in which CD8(+) T cell depletion is currently mandatory.
Yamada
Akira
A
Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Salama
Alan D
AD
Sho
Masayuki
M
Najafian
Nader
N
Ito
Toshiro
T
Forman
John P
JP
Kewalramani
Reshma
R
Sandner
Sigrid
S
Harada
Hiroshi
H
Clarkson
Michael R
MR
Mandelbrot
Didier A
DA
Sharpe
Arlene H
AH
Oshima
Hideo
H
Yagita
Hideo
H
Chalasani
Geetha
G
Lakkis
Fadi G
FG
Auchincloss
Hugh
H
Sayegh
Mohamed H
MH
D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D053282:CD27 Ligand; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D015536:Down-Regulation / Q000276:immunology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D007518:Isoantibodies / Q000096:biosynthesis / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D016042:Transplantation, Heterotopic / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D053282:CD27 Ligand; D018106:CD28 Antigens; C505772:Cd70 protein, mouse; D007518:Isoantibodies; D008565:Membrane Proteins; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7