Abstracts (complete list) - Wissenschaft Online

Kristin Hochweller, Jörg Striegler, Günter J Hämmerling, Natalio Garbi
Feed-back control of dendritic cell homeostasis
Dendritic cells (DCs) are pivotal coordinators of the immune system, governing the
choice between T cell immunity and tolerance. Despite their importance, the
mechanisms regulating the size of the DC compartment are largely unknown. In order
to investigate DC homeostasis we have developed a BAC transgenic mouse strain in
which CD11c+ DCs express the diphtheria toxin receptor (DTR). In this CD11c-DOG
strain, about 95% of DCs are depleted by a single DT application. Due to their fast turnover,
continuous DC depletion requires daily DT application.
Here we show that a residual fraction of DC progenitors can be induced to repopulate
the DC compartment using wild-type and CD11c-DOG mixed bone marrow chimeras in
which most of the DCs derive from CD11c-DOG bone marrow and, thus, can be
depleted by DT. These results indicate that there exist active homeostatic mechanisms
controlling the DC pool size. To investigated whether DC progenitors respond to the size
of the DC compartment by modulating their differentiation potential, we performed
competitive cotransfers of splenic DC progenitors obtained from mice with normal or
reduced DC numbers. About two thirds of the donor-derived DCs differentiated from
progenitors obtained from DC-deficient mice, indicating that a reduced number of DCs
leads to an increased activity of their precursors. The increased progenitor activity is
likely due to an increased frequency of DC progenitors in the spleen of DC-deplete mice
as suggested by colony forming assays in vitro in response to GM-CSF. Furthermore, a
reduced DC number also appears to increase the differentiation activity of DC
progenitors on a per-cell basis because the number of DCs recovered after transfer of
splenic DC progenitors from untreated mice into DC-deficient mice is ten times higher
than that obtained when the same precursors are transferred into mice with normal DC
numbers.
Thus, these results demonstrate that there are active homeostatic mechanisms
controlling the size of the DC compartment via a feedback loop whereby the number of
DCs controls the activity of their progenitors.