CD70 signaling is critical for CD28-independent CD8+ T cell-mediated alloimmune responses in vivo |
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Authors: | Yamada Akira Salama Alan D Sho Masayuki Najafian Nader Ito Toshiro Forman John P Kewalramani Reshma Sandner Sigrid Harada Hiroshi Clarkson Michael R Mandelbrot Didier A Sharpe Arlene H Oshima Hideo Yagita Hideo Chalasani Geetha Lakkis Fadi G Auchincloss Hugh Sayegh Mohamed H |
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Institution: | Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. |
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Abstract: | 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. |
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