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Schnorfeil, Frauke Marie (2011): MicroRNAs regulate Dendritic Cell Development and Function. Dissertation, LMU München: Faculty of Medicine
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Abstract

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.