CD70 expression by dendritic cells plays a critical role in the immunogenicity of CD40-independent, CD4+ T cell-dependent, licensed CD8+ T cell responses

Abstract

The stimulation of DC by CD4(+) T cells is known to condition DC to activate naïve CD8(+) T cells, predominantly via CD40-CD40L interactions. It has been proposed that a critical consequence of DC conditioning is the induction of CD70 expression. Whether and how CD70 induction contributes to CD8(+) T cell responses in the absence of CD40-CD40L interactions are unknown. CD8(+) T cell responses to adenoviral- or DC-based immunization of CD40-deficient mice revealed a CD40-independent, CD4(+) T cell-dependent pathway for CD70 induction on conventional DC. This pathway and subsequent CD8(+) T cell responses were enhanced by, but not dependent on, concomitant activation of TLR and in part, used TRANCE and LIGHT/LTalphabeta stimulation. Blocking TRANCE and LIGHT/LTalphabeta during stimulation reduced the immunogenicity of CD40-deficient DC. These data support the hypothesis that induction of CD70 expression on DC after an encounter with activated CD4(+) T cells is a major component of CD4(+) T cell-mediated licensing of DC. Further, multiple pathways exist for CD4(+) T cells to elicit CD70 expression on DC. These data in part explain the capacity of CD40-deficient mice to mount CD8(+) T cell responses and may provide additional targets for immunotherapy in situations when CD40-mediated licensing is compromised.

Differential Requirement for CD70 and CD80/CD86 in Dendritic Cell-Mediated Activation of Tumor-Tolerized CD8 T Cells

“…3 B ). We used anti-CD70 and anti-4-1BBL antibodies previously shown to block CD70/CD27 and 4-1BBL/4-1BB interactions i n vivo , to define the contribution of CD70 and 4-1BB in DC-mediated delay of tolerance induction (14, 24). To exclude possible Fc receptor (FcR)-mediated effect on the DCs, we generated F(ab’) 2 fragment of each antibody lacking the Fc portion of the molecule but still retaining binding activity as assessed by the ability to compete fluorescently labeled full length antibody for cell surface binding (Fig.…”

“…Where indicated, BMDCs were loaded with 1µg/mL SIY peptide for 1hr at 37°C and/or were labeled for 10 min at 37°C with 5µM CFSE (Invitrogen) in PBS plus 0.1% BSA on the day of harvest. For blocking experiments, 1×10 6 cell/mL were incubated in 10 µg/mL of F(ab’) 2 of indicated antibodies for 2.5 hours on ice, as previously described (14). BMDCs were rinsed and resuspended at 1×10 6 cells / 40μL PBS for intraprostatic injection (1×10 6 cells per mouse).…”

Self MHC class I–licensed NK cells enhance adaptive CD8 T-cell viral immunity

“…34 For analysis of the MCMV-specific CD8 T response over time, mice were bled at indicated times after infection and lymphocytes prepared from blood. All Ab stains were performed on ice.…”

LTβR signaling in dendritic cells induces a type I IFN response that is required for optimal clonal expansion of CD8+T cells

“…The variable requirement for CD40 in CD8 + T-cell cross-priming could be explained by the recent identification of CD40L expression on DCs which may drive CD8 + T-cell priming in more help-independent systems (34). Furthermore, CD70 has been shown to play a more predominant role in CD40-independent CD8 + T-cell responses (35). Given that the defects we observe in CD8 + T-cell clonal expansion are significant but not absolute (i.e., residual CD8 + T-cell proliferation is observed), a model of complex interplay of multiple TNF family receptors, rather than CD40 alone, in mediating DC licensing seems likely.…”