Dendritic cells as
a tool to combat infectious diseases
Institute
for Molecular Biology of Infectious Diseases, University of Würzburg,
Röntgenring
11, 97070 Würzburg, Germany
Dendritic cells
(DC) serve as sensors of infectious agents in peripheral tissues and have
the potential to stimulate resting T cells for initiation of the adaptive
immune response. Moreover, the activation of DC by microbial stimuli leads
to the production of cytokines which modulate the emerging T cell response.
Upon loading with microbial antigen, adoptively transferred DC stimulate effective
cell-mediated immunity to infections. This offers encouragement for the development
of DC-based immune intervention strategies against intracellular pathogens
such as Leishmania. However, the immunological mechanisms
underlying the strong adjuvant effect of DC are not fully understood and
there is a need to identify defined antigens with which to arm DC for the
induction of antimicrobial immunity. Therefore, we analyzed the role of DC-derived
IL-12 in the induction of resistance to Leishmania major,
and we evaluated the protective efficacy of DC loaded with individual Leishmania antigens. Epidermal Langerhans cells (LC) were used
as a source of DC. The inability of antigen-pulsed LC to release IL-12 completely
abrogated their capacity to mediate protection against leishmaniasis, suggesting
that the availability of donor LC-derived IL-12 is a requirement for the
development of a protective T cell response. In addition, we showed that
mice vaccinated with LC that had been pulsed with selected molecularly defined
parasite proteins are capable of controlling infection with L.
major and that the protective potential of DC pulsed with a given Leishmania antigen correlated with the level of their IL-12
expression. Analysis of the cytokine profile of mice after DC-based vaccination
revealed that protection was associated with a shift towards a Th1-type response.
Together, these findings emphasize the critical role of IL-12 in DC-mediated
vaccination and suggest that the development of DC-based immune interventions
for the prevention or treatment of infections is feasible.