MicroRNAs regulate Dendritic Cell Development and Function

Dendritic cells (DCs) play a key role in the initiation of adaptive
immune responses and the maintenance of self-tolerance. Due to
their therapeutic potential, understanding the mechanisms that
guide DC differentiation and effector functions is important. DC
differentiation and activation depends on transcription factor
control of stage-specific gene expression. The recent
identification of posttranscriptional control of gene expression by
microRNAs (miRNAs) has added another layer of gene regulation that
might be important in DC biology. We analyzed the miRNA expression
profiles of different DC subsets and identified several miRNAs
differentially expressed between plasmacytoid DCs (pDCs) and
conventional DCs (cDCs). In terms of miRNA expression, pDCs were
more closely related to CD4+ T cells than to cDCs. We also observed
that pDCs and cDCs preferentially expressed miRNAs associated with
lymphoid or myeloid lineage differentiation, respectively. By
knocking down miR-221 or miR-222 during in vitro DC
differentiation, we obtained a higher pDC frequency. While p27kip1
and c-kit are confirmed miR-221/222 targets, we additionally
identified the pDC cell fate regulator E2-2 as a potential
miR-221/222 target. Thus, our analysis points to a role for miRNAs
in directing and stabilizing pDC and cDC cell fate decisions. To
assess the general influence of miRNAs on DCs, we generated mice
with a DC-specific conditional knockout of the key miRNA-producing
enzyme Dicer. Dicer-deficient mice dis- played no alterations in
short-lived spleen and lymph node DCs. However, long-lived
epidermal DCs, known as Langerhans cells (LCs), showed increased
turnover and apoptosis rates, leading to their progressive loss.
Upon stimulation, Dicer-deficient LCs were able to properly
upregulate the surface molecules MHC class I and CCR7, but not MHC
class II, CD40 and CD86. In consequence, they were incapable of
stimulating CD4+ T cell proliferation. The work presented in this
thesis indicates a role for miRNAs in DC regulation not covered by
transcription factors. Having demonstrated a role for miRNAs in DC
lineage fate decisions, as well as in LC homeostasis, maturation
and function, we conclude that miRNAs regulate various aspects of
DC biology and thereby contribute to the control of adaptive immune
responses.