Abstract
BackgroundThe imidazoquinoline derivate imiquimod induces inflammatory responses and protection against transplanted tumors when applied to the skin in combination with a cognate peptide epitope (transcutaneous immunization, TCI). Here we investigated the role of regulatory T cells (Treg) and the suppressive cytokine IL-10 in restricting TCI-induced cytotoxic T lymphocyte (CTL) responses.Methodology/Principal FindingsTCI was performed with an ointment containing the TLR7 agonist imiquimod and a CTL epitope was applied to the depilated back skin of C57BL/6 mice. Using specific antibodies and FoxP3-diphteria toxin receptor transgenic (DEREG) mice, we interrogated inhibiting factors after TCI: by depleting FoxP3+ regulatory T cells we found that specific CTL-responses were greatly enhanced. Beyond this, in IL-10 deficient (IL-10-/-) mice or after blocking of IL-10 signalling with an IL-10 receptor specific antibody, the TCI induced CTL response is greatly enhanced indicating an important role for this cytokine in TCI. However, by transfer of Treg in IL-10-/- mice and the use of B cell deficient JHT-/- mice, we can exclude Treg and B cells as source of IL-10 in the setting of TCI.Conclusion/SignificanceWe identify Treg and IL-10 as two important and independently acting suppressors of CTL-responses induced by transcutaneous immunization. Advanced vaccination strategies inhibiting Treg function and IL-10 release may lead the development of effective vaccination protocols aiming at the induction of T cell responses suitable for the prophylaxis or treatment of persistent infections or tumors.
Highlights
The development of new vaccination methods to successfully combat malignant and infectious diseases is a central aim of present studies
Conclusion/Significance: We identify Treg and IL-10 as two important and independently acting suppressors of CTLresponses induced by transcutaneous immunization
One well-described route of suppression mediated by Treg is via the release of IL-10, which influences the production of proinflammatory cytokines by dendritic cells (DC) and macrophages
Summary
The development of new vaccination methods to successfully combat malignant and infectious diseases is a central aim of present studies. In this context transcutaneous immunization (TCI) approaches seem to be a promising strategy. An important step in the development and improvement of TCI is an enhanced understanding of the underlying mechanisms and limitations of TCI with imiquimod This might elicit the opportunity to increase inflammatory factors or circumvent suppressing influences. The imidazoquinoline derivate imiquimod induces inflammatory responses and protection against transplanted tumors when applied to the skin in combination with a cognate peptide epitope (transcutaneous immunization, TCI). We investigated the role of regulatory T cells (Treg) and the suppressive cytokine IL-10 in restricting TCI-induced cytotoxic T lymphocyte (CTL) responses
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