Biomedical subjects

Thomas Hieronymus

Publications and source records attributed to Thomas Hieronymus.

5 recordsLinked to original sources

PubMed2006

Towards an understanding of the transcription factor network of dendritic cell development.

Dendritic cells (DCs) are antigen-presenting cells of the immune system and develop from hematopoietic stem cells through successive steps of lineage commitment and differentiation. The three major DC populations are epidermal Langerhans cells, tissue/interstitial/dermal DCs and plasmacytoid DCs. We review how gene-targeted mutations in mice have contributed to our understanding of how the various DC subpopulations develop. These studies have revealed both overlapping and distinct pathways of DC differentiation and show that there is no obvious correlation between transcription factor knockout phenotypes and a lymphoid or myeloid origin of DCs.

Animals↗

PubMed2005

Progressive and controlled development of mouse dendritic cells from Flt3+CD11b+ progenitors in vitro.

Dendritic cells (DC) represent key regulators of the immune system, yet their development from hemopoietic precursors is poorly defined. In this study, we describe an in vitro system for amplification of a Flt3(+)CD11b(+) progenitor from mouse bone marrow with specific cytokines. Such progenitor cells develop into both CD11b(+) and CD11b(-) DC, and CD8alpha(+) and CD8alpha(-) DC in vivo. Furthermore, with GM-CSF, these progenitors synchronously differentiated into fully functional DC in vitro. This two-step culture system yields homogeneous populations of Flt3(+)CD11b(+) progenitor cells in high numbers and allows monitoring the consecutive steps of DC development in vitro under well-defined conditions. We used phenotypic and functional markers and transcriptional profiling by DNA microarrays to study the Flt3(+)CD11b(+) progenitor and differentiated DC. We report here on an extensive analysis of the surface Ag expression of Flt3(+)CD11b(+) progenitor cells and relate that to surface Ag expression of hemopoietic stem cells. Flt3(+)CD11b(+) progenitors studied exhibit a broad overlap of surface Ags with stem cells and express several stem cell Ags such as Flt3, IL-6R, c-kit/SCF receptor, and CD93/AA4.1, CD133/AC133, and CD49f/integrin alpha(6). Thus, Flt3(+)CD11b(+) progenitors express several stem cell surface Ags and develop into both CD11b(+) and CD11b(-) DC, and CD8alpha(+) and CD8alpha(-) DC in vivo, and thus into both of the main conventional DC subtypes.

Adoptive Transfer↗

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↗

PubMed2002

Hyporesponsiveness to gammac-chain cytokines in activated lymphocytes from patients with systemic lupus erythematosus leads to accelerated apoptosis.

Pathogenesis of autoimmune diseases like systemic lupus erythematosus (SLE) is unresolved. Dysregulation of programmed cell death is discussed as a pathogenetic factor. We have previously shown that increased in vitro apoptosis of cultured peripheral blood mononuclear cells (PBMC) is nonspecific for SLE. Importantly, however, in recent experiments with SLE PBMC from patients with infections and fever in vitro apoptosis was strongly accelerated. We therefore hypothesized that regulation of apoptosis might be disturbed in activated SLE lymphocytes. Thus, we generated phytohemagglutinine (PHA)/IL-2 stimulated lymphoblasts in vitro. These lymphoblasts readily undergo apoptosis after culture in cytokine-free medium, and can be rescued by addition of gammac-chain cytokines IL-2, -4, -7, or -15. In lymphoblasts from 60 SLE patients tested in comparison to lymphoblasts from normal donors cultured in parallel, we found significant hyporesponsiveness to gammac-chain cytokines in SLE cells. Minor differences were also seen in lymphoblasts from patients with other systemic autoimmunopathies (mixed connective tissue disease, vasculitis, n=49)and in lymphoblasts from patients with other autoimmune diseases (mainly rheumatoid or reactive arthritis, myositis, n=44). In patients with high erythrocyte sedimentation rate (> 25 mm/h), TNF-alpha (> 6.5 pg/ml) or IL-12 (> 4.7 pg/ml) serum levels or detectable IFN-gamma concentrations hyporesponsiveness to gammac-chain cytokines was even more pronounced in SLE lymphoblasts, but not in lymphoblasts from the other groups. Moreover, increased apoptosis was seen in lymphoblasts from SLE patients with decreased complement (C)4 or elevated dsDNA antibody levels. In conclusion, these data suggest that in SLE patients with increased inflammatory activity and/or Th1 dominance signaling through gammac-chain cytokine receptors is deteriorated, leading to facilitated apoptosis of activated lymphocytes and enlarged onflow of apoptotic material.

Adult↗

PubMed2002

The impact of c-met/scatter factor receptor on dendritic cell migration.

Dendritic cells (DC) are professional antigen-presenting cells that possess both migratory properties and potent T cell stimulatory activity, and that allow the uptake of antigenic material inperipheral tissues and its subsequent presentation in the T cell areas of lymphoid organs. Thus motility represents a central property that is required for DC function. Here we report on the expression of the receptor tyrosine kinase c-met in DC. c-Met is the high affinity receptor for scatter factor (SF)/hepatocyte growth factor, and ligand-activated c-met exhibits mitogenic, morphogenic andmotogenic activity in vivo and in vitro. c-Met is signaling competent in DC since it is effectively tyrosine phosphorylated in response to SF ligand. It is demonstrated here that ligand-activated c-met regulates DC adhesion to the extracellular matrix component laminin but leaves antigen presenting function unaffected. Importantly, in ear sheet explant experiments activationof c-met by ligand induces emigration of cutaneous DC (Langerhans cell, LC) from skin, but SF is not a chemoattractant factor for DC. Our results suggest an important role of the c-met/SF system in DC/LC migration.

Animals↗