Expression of Costimulatory Ligand CD70 on Steady-State Dendritic Cells Breaks CD8+ T Cell Tolerance and Permits Effective Immunity

Abstract

Steady-state dendritic cells (DCs) maintain peripheral T cell tolerance, whereas mature DCs generate immunity. CD70 is a costimulatory ligand acquired upon DC maturation. To determine its impact on T cell fate, we have generated mice that constitutively express CD70 in conventional DCs (cDCs). In these mice, naive CD4+ and CD8+ T cells spontaneously convert into effector cells. Administration of peptide without adjuvant, which is ordinarily tolerogenic, elicited tumor-eradicating CD8+ T cell responses and robust CD4+ T cell-independent memory. CD70 was also constitutively expressed in cDCs that inducibly present viral epitopes. In this case, tolerance induction was prevented as well. The antigen-presenting DCs generated protective immunity to virus infection and broke a pre-existing state of CD8+ T cell tolerance. Thus, the sole expression of CD70 by otherwise immature cDCs sufficed to convert CD8+ T cell tolerance into immunity, defining the importance of CD27-CD70 interactions at the interface between T cell and DC.

Definition of Key Variables for the Induction of Optimal NY-ESO-1–Specific T Cells in HLA Transgene Mice

“…5B). Blocking of CD70 caused a 6-to 7-fold reduction of tetramer + cells, which is in agreement with studies showing that CD27 provides crucial costimulation for CD8 + T cell differentiation and memory formation (7,34,35). Remarkably, CD8 T cell priming was abolished by blockade of CCL3 or its receptor CCR5, whereas neutralization of CCL4 inhibited priming by only ∼40%.…”

Differential Impact of CD27 and 4-1BB Costimulation on Effector and Memory CD8 T Cell Generation following Peptide Immunization

“…Interestingly, the requirement for 4-1BB costimulation during the primary response to influenza virus is greater during infection with a more virulent strain of virus, consistent with the higher expression of 4-1BB on activated T cells from mice bearing a higher viral load (13). Although the lack of CD27 signaling results in suboptimal CD8 T cell responses (12,(14)(15)(16)(17), deliberate triggering of CD27 by administration of soluble rCD70 (18) or through transgenic expression of CD70 on DCs (19) prevents tolerance induced by injection of a peptide Ag and allows the generation of a population of effector and memory CD8 T cells. Similarly, 4-1BB triggering was shown to prevent peptide-induced CD8 T cell tolerance (20) and augment effector and memory responses following peptide or DC immunization (21)(22)(23).…”

Dendritic cell-directed lentivector vaccine induces antigen-specific immune responses against murine melanoma

“…Many studies have demonstrated that anti-tumor immunity and the ability to break tolerance could be enhanced by co-delivering additional immunomodulator genes, such as interleukin-2, interleukin-12, interleukin-15, CD70 and other activators, to DCs. 5,[57][58][59][60] We are currently conducting experiments to evaluate the anti-tumor immunity generated by the co-delivery of a tumor antigen and an immuomodulator using this DC-directed lentivector system.…”