A subset of dendritic cells induces CD4+ T cells to produce IFN-γ by an IL-12–independent but CD70-dependent mechanism in vivo

Abstract

Interferon (IFN)-γ, a cytokine critical for resistance to infection and tumors, is produced by CD4+ helper T lymphocytes after stimulation by cultured dendritic cells (DCs) that secrete a cofactor, interleukin (IL)-12. We have identified a major IL-12–independent pathway whereby DCs induce IFN-γ–secreting T helper (Th)1 CD4+ T cells in vivo. This pathway requires the membrane-associated tumor necrosis family member CD70 and was identified by targeting the LACK antigen from Leishmania major within an antibody to CD205 (DEC-205), an uptake receptor on a subset of DCs. Another major DC subset, targeted with 33D1 anti-DCIR2 antibody, also induced IFN-γ in vivo but required IL-12, not CD70. Isolated CD205+ DCs expressed cell surface CD70 when presenting antigen to T cell receptor transgenic T cells, and this distinction was independent of maturation stimuli. CD70 was also essential for CD205+ DC function in vivo. Detection of the IL-12–independent IFN-γ pathway was obscured with nontargeted LACK, which was presented by both DC subsets. This in situ analysis points to CD70 as a decision maker for Th1 differentiation by CD205+ DCs, even in Th2-prone BALB/c animals and potentially in vaccine design. The results indicate that two DC subsets have innate propensities to differentially affect the Th1/Th2 balance in vivo and by distinct mechanisms.

Dendritic cells in cancer immunotherapy

“…In our 62-patient trial (our unpublished data), in metastatic melanoma, tumor-peptide-specific ex vivo detectable (Elispot, tetramer staining) IFN-g-producing CD4 1 T cells were regularly detectable. This is surprising given the low amounts of IL-12p70 released from cocktailmatured DC in vitro but may be explained by their expression of CD70 [20,54]. The vaccine-specific Th cells were FOXP3-negative, indicating that vaccine-specific natural Treg were not induced, which is counterintuitive to a previous report [55], yet compatible with recent Treg cloning data [56].…”

“…Our knowledge on the type of stimulus required in such a setting for optimal immunogenicity is expanding [18]. Differential expression of receptors might allow targeting of select DC subsets and ''tailor-made'' immunization [19,20]. Effective immunization was also observed following delivery of TLR ligand-antigen conjugates, which contain the maturation stimulus but are not as precise in cell targeting [21].…”

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

“…For Th1-cell polarization, IL-12p70 production by DCs is, besides the recently described CD70-dependent pathway [63], a clear signal toward Th1-cell polarization but signal 3 for Th2 cells remains less clear.…”

CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response

“…14–16 CD27, a member of the tumor necrosis factor receptor (TNFR) superfamily, is a costimulatory molecule expressed on naïve and activated CD4 + and CD8 + T cells 17 and is known to be important in T cell activation, 18 maturation, 19 cytokine secretion, 20 and survival, 21 making it a promising target for T cell-based immunomodulation. Recently, a novel, fully human anti-human CD27 monoclonal antibody (αhCD27) was developed which binds with high affinity to induce potent human T cell responses in the context of T cell receptor stimulation.…”