Antigen presenting dendritic cells (DC) represent highly specialized immune cells with a central role in immunity and tolerance induction. DC sense antigens, which are taken-up, processed and presented in the context of MHC molecules to elicit antigen specific T cell responses (Zenke and Hieronymus, 2006; Seré et al., 2012). Specific DC subsets exist that differ in surface phenotype, function, activation state and anatomical localization. The main DC subsets are (i) tissue/interstitial DC in organs, now referred to as conventional or classical DC (cDC); (ii) plasmacytoid DC (pDC) in blood that represent the major producers of type 1 interferon (iii) CD8alpha DC in lymphoid tissue and (iv) Langerhans cells (LC), the cutaneous contingent of DC in epidermis.

 

Langerhans cells of epidermal skin are stained
for MHC class II (green)

 

All DC subsets develop from hematopoietic stem cells via Flt3 expressing progenitors through consecutive steps of lineage commitment and differentiation. Surprisingly, DC development shows remarkable plasticity and DC can develop from both lymphoid and myeloid compartments. Additionally, a clonogenic DC progenitor for cDC and pDC was identified, referred to as Flt3+M-CSFR+c-kitlow common DC progenitor (CDP). The laboratory studies DC development by employing in vitro culture systems and knockout mouse models (Hacker et al., 2003; Hieronymus et al., 2005; Ju et al., 2007; Felker et al., 2010; Seré et al., 2012).

 

Hematopoietic stem cells (HSC) develop into DC subsets through consecutive steps of lineage commitment and differentiation.

 



Multipotent progenitors (MPP) and common dendritic progenitors (CDP) develop in bone marrow cultures of Flt3 ligand, SCF, hyper-IL-6 and IGF-1 and are analyzed by flow cytometry (Felker et al., 2010, top).

CDP exhibit a DC-primed gene expression repertoire as demonstrated by gene expression profiling and hierarchical cluster analysis (Felker et al., 2010). Red, high expression; blue, low expression; white, intermediate expression (left).

 

We found that (i) CDP exhibit a DC-primed gene expression repertoire and (ii) TGFbeta1 impacts on CDP and directs their differentiation towards cDC. Gene expression profiling of TGFbeta1-induced genes identified instructive transcription factors for cDC subset specification, such as interferon regulatory factor-4 (IRF-4) and RelB. TGFbeta1 also induced the transcription factor Id2 that suppresses pDC development. Thus, TGFbeta1 directs CDP differentiation into cDC by inducing both cDC instructive factors and pDC inhibitory factors.

 

Hematopoietic stem cells and LC precursors in skin develop into long-term LC in steady state, which requires the transcription factor Id2 (A, top panel). In inflammation Gr-1+ monocytes develop into short-term LC, which does not require Id2 (A, lower panel). LC development in inflammation occurs in consecutive waves of short-term LC and long-term LC (B).

 

The helix-loop-helix transcription factor Id2 represents a determining factor for DC development (Hacker et al., 2003; Zenke and Hieronymus, 2006; Seré et al., 2012). Id2-/- mice lack Langerhans cells (LC), the cutaneous contingent of DC, and a specific splenic DC subset. TGFbeta1-/- mice also lack LC and we show that TGFbeta1 acts upstream of Id2 and induces Id2 expression.

 

We now identified two types of LC: short-term LC and long-term LC cells (Seré et al., 2012). Short-term LC develop from Gr-1+ monocytes under inflammatory conditions and are Id2-independent. Long-term LC arise from bone marrow under steady state and depend on Id2. LC reconstitution after inflammation occurs in two waves: an initial fast wave of Gr-1+ monocyte-derived short-term LC, which is followed by a second wave of bone marrow-derived long-term LC.

 

Selected publications:

Analysis of computational footprinting methods for DNase sequencing experiments.
Gusmao, E. G., Allhoff, M., Zenke, M., and Costa, I. G. (2016).
Nature Methods 13, 303-309 (see also Editorial Nature Methods 13, 185)  Abstract Full
 
Epigenetic program and transcription factor circuitry of dendritic cell development.
Lin, Q., Chauvistré, H., Costa, I. G., Gusmão, E. G., Mitzka, S., Haenzelmann, S., Baying, B., Klisch, T., Moriggl, R., Hennuy, B., Smeets, H., Hoffmann, K., Benes, V., Seré, K., and Zenke, M. (2015).
Nucl. Acid Res. 43, 9680-9693.  Abstract Full
 
Distinct murine mucosal Langerhans cell subsets develop from pre-dendritic cells and monocytes
Capucha, T., Mizraji, G., Segev, H., Blecher-Gonen, R., Winter, D., Khalaileh, A., Tabib, Y., Attal, T., Nassar, M., Zelentsova, K., Kisos, H., Zenke, M., Seré, K., Hieronymus, T., Burstyn-Cohen, T., Amit, I., Wilensky, A. and Hovav, A.H. (2015).
Immunity 43, 369-381  Abstract Full
 
The clash of Langerhans cell homeostasis: Should I stay or should I go?
Hieronymus, T., Zenke, M., Baek, J. H., Seré K. (2014).
Semin. Cell Dev. Biol., S1084-9521. Abstract | Full
 
Dendritic cell development requires histone deacetylase activity.
Chauvistré, H., Küstermann, C., Rehage, N., Klisch, T., Mitzka, S., Felker, P., Rose-John, S., Zenke, M., and Seré, K. (2014).
Eur. J. Immunol. 44, 2478-2488.
 
Two distinct types of Langerhans cells populate the skin during steady state and inflammation.
Seré, K., Baek, J. H., Ober-Blöbaum, J., Müller-Newen, G., Tacke, F., Yokota, Y., Zenke, M., and Hieronymus, T. (2012).
Immunity 37, 905-916.
 
The HGF receptor/met tyrosine kinase is a key regulator of dendritic cell migration in skin immunity.
Baek, J. H., Birchmeier, C., Zenke, M., and Hieronymus, T. (2012).
J. Immunol. 189, 1699-1707.
 
TGF-ß1 accelerates dendritic cell differentiation from common dendritic cell progenitors and directs subset specification toward conventional dendritic cells.
Felker, P., Seré, K., Lin, Q., Becker, C., Hristov, M., Hieronymus, T., and Zenke, M. (2010).
J. Immunol. 185, 5326-5335.
 
The role of multiple toll-like receptor signalling cascades on interactions between biomedical polymers and dendritic cells.
Shokouhi, B., Coban, C., Hasirci, V., Aydin, E., Dhanasingh, A., Shi, N, Koyama, S., Akira, S., Zenke, M., and Sechi, A. S. (2010).
Biomaterials 31, 5759-5771.
 
Transforming growth factor beta1 up-regulates interferon regulatory factor 8 during dendritic cell development.
Ju, X.-S., Ruau, D., Jäntti, P., Sere, K., Becker, C., Wiercinska, E., Bartz, C., Erdmann, B., Dooley, S., and Zenke, M. (2007).
Eur. J. Immunol. 37, 1174-1183.
 
Towards an understanding of the transcription factor network of dendritic cell development.
Zenke, M., and Hieronymus, T. (2006).
Trends Immunol. 27, 140-145.
 
Progressive and controlled development of mouse dendritic cells from Flt3+CD11b+ progenitors in vitro.
Hieronymus, T., Gust, T. C., Kirsch, R. D., Jorgas, T., Blendinger, G., Goncharenko, M., Supplitt, K., Rose-John, S., Muller, A. M., and Zenke, M. (2005).
J. Immunol. 174, 2552-2562.
 
RNA-containing adenovirus/polyethylenimine transfer complexes effectively transduce dendritic cells and induce antigen-specific T cell responses.
Gust, T. C., Diebold, S. S., Cotten, M., and Zenke, M. (2004).
J. Gene Med. 6, 464-470.
Abstract | Full
 
Transcriptional profiling identifies Id2 function in dendritic cell development.
Hacker. C., Kirsch, R. D., Ju, X.-S., Hieronymus, T., Gust, T. C., Kuhl, C., Jorgas, T., Kurz, S. M., Rose-John, S., Yokota, Y., and Zenke, M. (2003).
Nat. Immunol. 4, 380-386.
 
MHC class II presentation of endogenously expressed antigens by transfected dendritic cells.
Diebold, S. S., Cotten, M., Koch, N., and Zenke, M. (2001).
Gene Ther. 8, 487-493.
Abstract| Full
 
Polarised expression pattern of focal contact proteins in highly motile antigen presenting dendritic cells.
Madruga, J., Koritschoner, N. P., Diebold, S. S., Kurz, S. M., and Zenke, M. (1999).
J. Cell Sci. 112, 1685-1696.
Abstract | Full
 
Dendritic cell progenitor is transformed by a conditional v-Rel estrogen receptor fusion protein v-RelER.
Boehmelt, G., Madruga, J., Dorfler, P., Briegel, K., Schwarz, H., Enrietto, P. J., and Zenke, M. (1995).
Cell 80, 341-352.
Abstract | Full