Abstract
Despite the success of vaccines against some microbial pathogens, their utility in the prevention and treatment of cancer has thus far been limited. We have previously demonstrated that vaccination with dendritic cells activated with the TLR-4 ligand LPS and IFN-γ promotes an antigen-specific anti-tumor response that prevents tumor recurrence. To evaluate this mechanistically, we here studied the effects of this TLR-activated DC on regulatory T cell activity. Dendritic cells activated with LPS and IFN- γ negated the effects of regulatory T cells on responder cell proliferation. Restoration of responder cell proliferation was noted when TLR-activated dendritic cells were separated from both regulators and responders by a semi-permeable membrane. The effect is therefore mediated by a soluble factor but was independent of both IL-6 and IL-12. Furthermore, the soluble mediator appeared to act at least in part on the regulators themselves rather than responder cells exclusively. Because recent studies have demonstrated conversion of T regulatory cells into IL-17-producing effectors, we further questioned whether the TLR-activated dendritic cell would induce cytokine production and effector function in our system. We found that regulators produced a substantial amount of IFN- γ in the presence of TLR-activated dendritic cells but not immature dendritic cells. IFN-γ production was associated with upregulation of the Th1 transcriptional regulator T-bet, and a significant fraction of IFN-γ-producing regulators coexpressed T-bet and FoxP3. While the effects of the LPS-activated dendritic cell on responder cell proliferation were IL-12 independent, upregulation of T-bet was inhibited by a neutralizing anti-IL-12 antibody. Collectively, these and prior data suggest that varying innate immune signals may direct the phenotype of the immune response in part by inhibiting suppressor T cells and promoting differentiation of these regulators into particular subsets of effectors.
Highlights
Dendritic cells act as surveyors highly active in antigen uptake, processing, and presentation, and they are responsible for the sensitization of naıve T cells [1,2,3]
We have previously demonstrated that tumor antigen-bearing dendritic cells generated using IFN-c and the TLR-4 agonist LPS promote a targeted immune response in patients with ductal carcinoma in situ [13]
We compared the capacity of human CD4+CD25+ T cells to inhibit the proliferation of CD4 and CD8 lymphocytes to TCR stimulation in the presence of immature dendritic cells versus DC1 dendritic cells. 1.256105 sorted CD4+CD25+ T cells were combined with 2.56105 CFSE-labeled unfractionated lymphocytes (CD4 and CD8 positive) and 16105 immature dendritic cells
Summary
Dendritic cells act as surveyors highly active in antigen uptake, processing, and presentation, and they are responsible for the sensitization of naıve T cells [1,2,3]. The role of the dendritic cell in the initiation of the immune response has been magnified through the discovery of pattern recognition receptors [4,5]. It is clear that presenting cells bear receptors (including Toll-like receptors [TLR]) that recognize generalized molecular patterns shared by various classes of microorganisms. Signaling through Toll-like receptors activates the immune response through multiple mechanisms; Toll ligands activate presenting cells, and inhibit regulatory cells that otherwise suppress the adaptive response. A proposed breakthrough for anti-tumor vaccines was the utilization of tumor antigen-bearing dendritic cells. Given their central role in initiating immunity, administration of dendritic cells bearing tumor peptides carries the potential to generate a vigorous tumor-specific immune response. Dendritic cells have been used as immunotherapeutics in multiple clinical trials with varying success, and ideal strategies for activating, targeting, and delivering these cells are not yet fully elucidated [12]
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