Biomedical subjects

Christine Hacker

Publications and source records attributed to Christine Hacker.

4 recordsLinked to original sources

PubMed2004

Immunoglobulin-like transcripts ILT2, ILT3 and ILT7 are expressed by human dendritic cells and down-regulated following activation.

Immunoglobulin-like transcripts (ILT) represent novel immunoglobulin superfamily receptors that are expressed in myeloid, lymphoid and dendritic cells (DC). Here, we studied by gene expression profiling with DNA microarrays ILT expression in different DC subsets, including plasmacytoid DC (PDC), monocyte-derived DC (Mo-DC) and DC obtained by in vitro differentiation from CD34(+) progenitor cells, and DC activated in the presence of different activating agents. ILT2 and ILT3 were expressed in PDC, Mo-DC and DC obtained from CD34(+) cells. ILT7 mRNA was present in PDC, but absent in Mo-DC and DC obtained from CD34(+) cells, indicating that ILT7 mRNA expression seems to be a marker for PDC. CpG-DNA and inflammatory stimuli, such as TNF alpha, prostaglandin E2 (PGE2) and soluble CD40 ligand (sCD40L), and different combinations thereof are frequently employed for DC activation. Here, we demonstrate that ILT2 and ILT3 expression is down-regulated following DC activation by CpG-DNA and inflammatory stimuli at both mRNA and protein levels. Thus, activation of human DC with such stimuli involves down-regulation of inhibitory ILT2 and ILT3 receptors, and this could represent a novel mechanism contributing to DC activation.

Antigens, CD↗

PubMed2003

Transcriptional profiling identifies Id2 function in dendritic cell development.

Dendritic cells (DCs) are potent antigen-presenting cells with a pivotal role in antigen-specific immune responses. Here, we found that the helix-loop-helix transcription factor Id2 is up-regulated during DC development in vitro and crucial for the development of distinct DC subsets in vivo. Id2-/- mice lack Langerhans cells (LCs), the cutaneous contingent of DCs, and the splenic CD8alpha+ DC subset is markedly reduced. Mice deficient for transforming growth factor (TGF)-beta also lack LCs, and we demonstrate here that, in DCs, TGF-beta induces Id2 expression. We also show that Id2 represses B cell genes in DCs. These findings reveal a TGF-beta-Id2 signaling pathway in DCs and suggest a mechanism by which Id2 affects the lineage choice of B cell and DC progenitors.

B-Lymphocytes↗

PubMed2003

Towards determining the differentiation program of antigen-presenting dendritic cells by transcriptional profiling.

Dendritic cells (DC) represent professional antigen-presenting cells that develop from hematopoietic progenitors through successive steps of differentiation. Employing DNA microarray technology, we analysed the specific changes in gene expression that occur when human progenitor cells differentiate into DC. CD34 progenitor cells were first amplified in vitro with stem cell factor (SCF), Flt3 ligand (FL), thrombopoietin and IL-6/soluble IL-6 receptor fusion protein, and cells were then induced to differentiate into DC with IL-4 and GM-CSF. DC maturation was induced by TNFalpha. Progenitor cells and DC were subjected to transcriptional profiling by DNA microarrays that represent 13000 human genes. Our analysis revealed specific changes in the expression of a large number of cell surface antigens including molecules involved in antigen uptake and processing, cell migration and antigen presentation. Genes encoding such molecules were upregulated during DC differentiation as were genes encoding cytokines, cytokine receptors, chemokines and chemokine receptors. Stem cell genes and genes related to the multilineage differentiation potential and proliferative state of progenitor cells were downregulated. Our analysis also provides information on the expression profiles of transcriptional regulators such as the NF-kappaB/rel and STAT transcription factors. Interestingly, NF-kappaB/rel factors were found to be expressed in both progenitor cells and DC at similar levels and were induced by TNFalpha. In contrast, expression of STAT factors increased during DC differentiation and their expression was virtually unaffected by TNFalpha.

Antigens, CD↗

PubMed2002

Nuclear factor kappaB-dependent gene expression profiling of Hodgkin's disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity.

Constitutive nuclear nuclear factor (NF)-kappaB activity is observed in a variety of hematopoietic and solid tumors. Given the distinctive role of constitutive NF-kappaB for Hodgkin and Reed-Sternberg (HRS) cell viability, we performed molecular profiling in two Hodgkin's disease (HD) cell lines to identify NF-kappaB target genes. We recognized 45 genes whose expression in both cell lines was regulated by NF-kappaB. The NF-kappaB-dependent gene profile comprises chemokines, cytokines, receptors, apoptotic regulators, intracellular signaling molecules, and transcription factors, the majority of which maintain a marker-like expression in HRS cells. Remarkably, we found 17 novel NF-kappaB target genes. Using chromatin immunoprecipitation we demonstrate that NF-kappaB is recruited directly to the promoters of several target genes, including signal transducer and activator of transcription (STAT)5a, interleukin-13, and CC chemokine receptor 7. Intriguingly, NF-kappaB positively regulates STAT5a expression and signaling pathways in HRS cells, and promotes its persistent activation. In fact, STAT5a overexpression was found in most tumor cells of tested patients with classical HD, indicating a critical role for HD. The gene profile underscores a central role of NF-kappaB in the pathogenesis of HD and potentially of other tumors with constitutive NF-kappaB activation.

Base Sequence↗