Project Details
Description
Our immune system develops from hematopoietic stem cells, which through sequential steps commit into mature effector cells. These processes are tightly regulated by cytokines and transcription factors that enforce lineage decisions. Our main objective focusses on the development and function of the lymphoid compartment, including T, B, Natural Killer (NK), and Dendritic Cells (DC) (Blom & Spits, Annu Rev Immunol. 2006). The cytokines that we consider of interest in this context include IL-7, TSLP, FLT3L, IL-15, and IL-21. The families of transcription factors that we study include members of the STAT, Notch, GATA, and Ets families.
The plasmacytoid DC (pDC) versus T-cell lineage decision in the human thymus is controlled by the balance between the transcription factors Spi-B and GATA-3. Engagement of Notch1, required for T cell development, by Delta-like1 downregulates Spi-B expression, while it induces GATA-3 levels. Consequently, Notch triggering blocks pDC development from progenitor cells, but this can be rescued by ectopically expressing Spi-B (Dontje et al., Blood, 2006).
PDCs are the major type I IFN producing cells after engagement by virusses or TLR agonists. PDC localize among others in the thymus where T cells develop from hematopoietic progenitor cells. We have shown that IFN-alpha strongly impairs development of progenitor cells into T-cells at the level of IL-7R signaling (Schmidlin et al., Blood, 2006). In addition, we showed that thymic pDCs, but not peripheral pDCs, constitutively produce IFN-alpha, which may help to control T cell development (Colantonio et al., Plos One, 2011).
We identified that the transcription factor Spi-B is key in the development of hematopoietic progenitor cells into pDCs (Schotte et al., J Exp Med, 2004). More recent we showed that Spi-B directly regulates the anti-apoptotic gene Bcl2-A1 (Karrich et al., Blood, 2012). Furthermore, we reported that the cytokine IL-21, which is mainly produced by activated CD4+ T cells, stimulates pDCs to secrete high levels of Granzyme B (Karrich et al., Blood, 2013). Granzyme B directly affects the proliferation of T cells and hence may be used in a negative feedback loop to downregulate T cell responses.
A novel layer of regulation that we investigate in pDCs involves the role of microRNAs, which are an evolutionary conserved class of endogenous ~19 to 23-nucleotides long non-coding RNAs.19 They act by repressing gene expression through targeting of the 3’-untranslated region (UTR) of mRNAs resulting in either mRNA degradation or translation inhibition, or a combination of both. We observed that miRNA-146a expression is induced upon TLR triggering and consequently interferes with type I IFN production as well as maturation and survival of pDCs (Karrich et al., Blood in press).
Theme: Infection and Immunity
The plasmacytoid DC (pDC) versus T-cell lineage decision in the human thymus is controlled by the balance between the transcription factors Spi-B and GATA-3. Engagement of Notch1, required for T cell development, by Delta-like1 downregulates Spi-B expression, while it induces GATA-3 levels. Consequently, Notch triggering blocks pDC development from progenitor cells, but this can be rescued by ectopically expressing Spi-B (Dontje et al., Blood, 2006).
PDCs are the major type I IFN producing cells after engagement by virusses or TLR agonists. PDC localize among others in the thymus where T cells develop from hematopoietic progenitor cells. We have shown that IFN-alpha strongly impairs development of progenitor cells into T-cells at the level of IL-7R signaling (Schmidlin et al., Blood, 2006). In addition, we showed that thymic pDCs, but not peripheral pDCs, constitutively produce IFN-alpha, which may help to control T cell development (Colantonio et al., Plos One, 2011).
We identified that the transcription factor Spi-B is key in the development of hematopoietic progenitor cells into pDCs (Schotte et al., J Exp Med, 2004). More recent we showed that Spi-B directly regulates the anti-apoptotic gene Bcl2-A1 (Karrich et al., Blood, 2012). Furthermore, we reported that the cytokine IL-21, which is mainly produced by activated CD4+ T cells, stimulates pDCs to secrete high levels of Granzyme B (Karrich et al., Blood, 2013). Granzyme B directly affects the proliferation of T cells and hence may be used in a negative feedback loop to downregulate T cell responses.
A novel layer of regulation that we investigate in pDCs involves the role of microRNAs, which are an evolutionary conserved class of endogenous ~19 to 23-nucleotides long non-coding RNAs.19 They act by repressing gene expression through targeting of the 3’-untranslated region (UTR) of mRNAs resulting in either mRNA degradation or translation inhibition, or a combination of both. We observed that miRNA-146a expression is induced upon TLR triggering and consequently interferes with type I IFN production as well as maturation and survival of pDCs (Karrich et al., Blood in press).
Theme: Infection and Immunity
| Status | Active |
|---|---|
| Effective start/end date | 1/01/2007 → … |