CD70 Signaling Is Critical for CD28-Independent CD8+ T Cell-Mediated Alloimmune Responses In Vivo

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.

CD27 Instructs CD4+ T Cells to Provide Help for the Memory CD8+ T Cell Response after Protein Immunization

“…In agreement with the abovementioned effects of CD70, CD27 was found to complement CD28 in promoting the primary CD8 ϩ T cell response in influenza virus infection and allograft models (21,22). CD27 protects primed T cells from apoptosis and thus increases the size of the effector CD8 ϩ T cell pool at priming and tissue sites (21).…”

Intracellular Signals of T Cell Costimulation

“…During development of memory T cell, CD28 and herpesvirus entry mediator (HVEM) are constitutively expressed on naïve T cells, which may control initial activation and division. CD27 is upregulated quickly; they can regulate clonal expansion (80). OX40 and 4-1BB are induced later, which prevent apoptosis and regulate the persistence of effector cells.…”

Schädigung respiratorischer Epithelzellen nach allogener Stammzelltransplantation in einem Zellkulturmodell der Graft versus Host Reaktion

“…Ebenso sindüberwiegend aus Studien nach soliden Organtransplantationen auch von einer klassischen Kostimulation unabhängige Beispiele von Abstoßungsreaktionen bekannt, sowie auch durch CD70-, CD95-oder NKG2D-vermittelte kostimulatorische Signale, die in zytotoxischen T-Zellen nachgewiesen werden konnten [46,58,59,60,61]. Yamada [62] …”