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Medical Research Council Center for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, United Kingdom
Dendritic cells (DCs) are the sentinels of the immune system, able
to interact with both naive and memory T cells. The recent observation
that DCs can ingest cells dying by apoptosis has raised the possibility
that DCs may, in fact, present self-derived Ags, initiating both
autoimmunity and tumor-specific responses, especially if associated
with appropriate danger signals. Although the process of ingestion of
apoptotic cells has not been shown to induce DC maturation, the exact
fate of these phagocytosing DCs remains unclear. In this paper we
demonstrate that DCs that ingest apoptotic cells are able to produce
TNF-
but have a diminished ability to produce IL-12 in response to
external stimuli, a property that corresponds to a failure to
up-regulate CD86. By single-cell analysis we demonstrate that these
inhibitory effects are restricted to those DCs that have engulfed
apoptotic cells, with bystander DCs remaining unaffected. These changes
were independent of the production of anti-inflammatory cytokines
TGF-
1 and IL-10 and corresponded with a diminished capacity to
stimulate naive T cells. Thus, the ingestion of apoptotic cells is not
an immunologically null event but is capable of modulating DC
maturation. These results have important implications for our
understanding of the role of clearance of dying cells by DCs not only
in the normal resolution of inflammation but also in control of
subsequent immune responses to apoptotic cell-derived
Ags.
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