The STATs on Dendritic Cell Development
2008; Cell Press; Volume: 28; Issue: 4 Linguagem: Inglês
10.1016/j.immuni.2008.03.006
ISSN1097-4180
AutoresNobuyuki Onai, Markus G. Manz,
Tópico(s)T-cell and B-cell Immunology
ResumoDendritic cells are a heterogeneous group of antigen presenting cells. In this issue of Immunity, Esashi et al., 2008Esashi E. Wang Y.H. Perng O. Liu Y.J. Watowich S.S. Immunity. 2008; 28 (this issue): 509-520Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar demonstrate how cytokine-receptor-regulated downstream transcription factors direct dendritic cell subpopulation differentiation from hematopoietic progenitor cells. Dendritic cells are a heterogeneous group of antigen presenting cells. In this issue of Immunity, Esashi et al., 2008Esashi E. Wang Y.H. Perng O. Liu Y.J. Watowich S.S. Immunity. 2008; 28 (this issue): 509-520Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar demonstrate how cytokine-receptor-regulated downstream transcription factors direct dendritic cell subpopulation differentiation from hematopoietic progenitor cells. Dendritic cells (DCs) are central regulators in both priming of innate and adaptive immune responses and in maintaining self-tolerance. Multiple DC subsets have been identified on the basis of their phenotype, location, maturation state, and functional properties (Shortman and Naik, 2007Shortman K. Naik S.H. Nat. Rev. Immunol. 2007; 7: 19-30Crossref PubMed Scopus (923) Google Scholar). In steady-state mouse lymphoid tissues, DCs can be classified in at least two main populations, "plasmacytoid" DCs (pDCs) and conventional DCs (cDCs), which can further be subdivided into three subsets on the basis of surface-molecule expression. Most steady-state lymphoid tissue DCs have a half-life of only few days and do not self-renew, and therefore they continuously need to be replaced by bone-marrow hematopoietic stem cells via respective developmental intermediates, i.e., hematopoietic progenitor cells. How is DC differentiation and maintenance from hematopoietic stem cells guided in steady state and disease, what are the developmental intermediates, and which environmental factors are critical? Furthermore, how do these environmental factors translate molecularly in progenitors to shape the transcriptional program, thereby leading to proliferation, differentiation, correct location, and finally function of DCs? Substantial knowledge on all these questions has been acquired over the last years. Granulocyte-macrophage colony stimulating factor (GM-CSF) with or without interleukin-4 was first demonstrated to lead to in vitro DC differentiation from whole bone-marrow cells or monocytes in both mice and man, and this efficient method of DC generation is now frequently used in both laboratory research and clinical applications. However, only Flt3-ligand stimulation of bone-marrow progenitors induces generation of both pDCs and cDCs, resembling DC populations in lymphoid organs, whereas addition of GM-CSF (with or without TNFα) to cultures blocks pDC development (Gilliet et al., 2002Gilliet M. Boonstra A. Paturel C. Antonenko S. Xu X.L. Trinchieri G. O'Garra A. Liu Y.J. J. Exp. Med. 2002; 195: 953-958Crossref PubMed Scopus (431) Google Scholar), a finding later confirmed in human hematopoietic progenitor cells. Furthermore, macrophage-colony stimulating factor (M-CSF) was most recently shown to enhance both in vitro pDC and cDC differentiation from mouse progenitor cells, especially when combined with Flt3-ligand stimulation (Fancke et al., 2008Fancke B. Suter M. Hochrein H. O'Keeffe M. Blood. 2008; 111: 150-159Crossref PubMed Scopus (80) Google Scholar, Onai et al., 2007Onai N. Obata-Onai A. Schmid M.A. Ohteki T. Jarrossay D. Manz M.G. Nat. Immunol. 2007; 8: 1207-1216Crossref PubMed Scopus (493) Google Scholar). Mice with targeted deletions of the genes encoding GM-CSF, M-CSF, or Flt3-ligand and mice with the respective receptor deletions have been generated. Both GM-CSF and M-CSF and respective receptor null mice have normal or slightly reduced lymphoid-tissue DC numbers, with only epidermal dendritic cells (Langerhans cells) being not produced from M-CSFR-deficient cells, and are thus dispensable for steady-state lymphoid-organ DC generation (Shortman and Naik, 2007Shortman K. Naik S.H. Nat. Rev. Immunol. 2007; 7: 19-30Crossref PubMed Scopus (923) Google Scholar). In contrast, Flt3-ligand-deficient mice have approximately one-tenth the numbers of lymphoid-tissue pDCs and cDCs, defining Flt3-ligand as a nonredundant cytokine for in vivo steady-state lymphoid-organ DC maintenance (McKenna et al., 2000McKenna H.J. Stocking K.L. Miller R.E. Brasel K. De Smedt T. Maraskovsky E. Maliszewski C.R. Lynch D.H. Smith J. Pulendran B. et al.Blood. 2000; 95: 3489-3497Crossref PubMed Google Scholar). Interestingly, bone-marrow dendritic cell progenitors as well as steady-state lymphoid-organ dendritic cells express the respective receptors for all three cytokines (Flt3 ligand, GM-CSF, and M-CSF) and are able to respond to each of them (Onai et al., 2007Onai N. Obata-Onai A. Schmid M.A. Ohteki T. Jarrossay D. Manz M.G. Nat. Immunol. 2007; 8: 1207-1216Crossref PubMed Scopus (493) Google Scholar, Shortman and Naik, 2007Shortman K. Naik S.H. Nat. Rev. Immunol. 2007; 7: 19-30Crossref PubMed Scopus (923) Google Scholar). A recent article in Immunity (Laouar et al., 2003Laouar Y. Welte T. Fu X.Y. Flavell R.A. Immunity. 2003; 19: 903-912Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar) and the work by Esashi et al., 2008Esashi E. Wang Y.H. Perng O. Liu Y.J. Watowich S.S. Immunity. 2008; 28 (this issue): 509-520Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar in this issue provide understanding of how Flt3-ligand and GM-CSF-mediated signals are integrated at the point of transcription to guide DC subtype differentiation from dendritic cell progenitors via differential activation of signal transducer and activator of transcription (STAT) factors, whereas M-CSF downstream signaling in DC development remains to be determined. Laouar et al., 2003Laouar Y. Welte T. Fu X.Y. Flavell R.A. Immunity. 2003; 19: 903-912Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar demonstrates that hematopoiesis-confined STAT3 deficiency leads to reduction of steady-state DCs to one-tenth the numbers of wild-type mice (resembling the phenotype of Flt3-ligand-deficient mice). This DC deficiency is not overcome by either Flt3-ligand injection or in vivo lipopolysaccharide induced general inflammation. Furthermore, they show that STAT3 is activated downstream of Flt3, thus demonstrating that STAT3 is required for Flt3-ligand-dependent DC differentiation, a process probably executed via transcriptional activation of DC differentiation supporting factors such as e.g., Spi-B, PU.1, and IRF-7 (Onai et al., 2006Onai N. Obata-Onai A. Tussiwand R. Lanzavecchia A. Manz M.G. J. Exp. Med. 2006; 203: 227-238Crossref PubMed Scopus (127) Google Scholar, Zenke and Hieronymus, 2006Zenke M. Hieronymus T. Trends Immunol. 2006; 27: 140-145Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). In contrast, GM-CSF-driven in vitro cDC development is not inhibited by STAT3 deficiency (Laouar et al., 2003Laouar Y. Welte T. Fu X.Y. Flavell R.A. Immunity. 2003; 19: 903-912Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar). Further weight to the idea that STAT3 is an important DC differentiation factor is given by the finding that enforced expression and activation of STAT3 in hematopoietic progenitors normally lacking DC potential instructs differentiation into both pDCs and cDCs (Onai et al., 2006Onai N. Obata-Onai A. Tussiwand R. Lanzavecchia A. Manz M.G. J. Exp. Med. 2006; 203: 227-238Crossref PubMed Scopus (127) Google Scholar). By using STAT3- and STAT5-deficient hematopoietic cells in in vitro and in vivo assays, Esashi et al., 2008Esashi E. Wang Y.H. Perng O. Liu Y.J. Watowich S.S. Immunity. 2008; 28 (this issue): 509-520Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar now elegantly provide the explanation of why GM-CSF as a single cytokine or as addition to Flt3-ligand cultures inhibits pDC and favors cDC development (Gilliet et al., 2002Gilliet M. Boonstra A. Paturel C. Antonenko S. Xu X.L. Trinchieri G. O'Garra A. Liu Y.J. J. Exp. Med. 2002; 195: 953-958Crossref PubMed Scopus (431) Google Scholar): GM-CSF activates STAT5, which in turn directly inhibits transcription of IRF-8 (also called interferon consensus binding protein [ICSBP]), a protein previously demonstrated to be essential for the development of pDCs and CD8α+CD4− cDCs in vivo (Schiavoni et al., 2002Schiavoni G. Mattei F. Sestili P. Borghi P. Venditti M. Morse 3rd, H.C. Belardelli F. Gabriele L. J. Exp. Med. 2002; 196: 1415-1425Crossref PubMed Scopus (321) Google Scholar). Also, they demonstrate that GM-CSF-mediated STAT5 activation, directly or indirectly, leads to inhibition of the transcription factors Spi-B and IRF-7, the cytokine receptor Flt3, and the pathogen-recognition receptor TLR9, all shown to be important in pDC differentiation and function (Shortman and Naik, 2007Shortman K. Naik S.H. Nat. Rev. Immunol. 2007; 7: 19-30Crossref PubMed Scopus (923) Google Scholar, Zenke and Hieronymus, 2006Zenke M. Hieronymus T. Trends Immunol. 2006; 27: 140-145Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). However, besides activation of STAT5, GM-CSF also leads to activation of STAT3 and expression of IRF-4, a transcription factor important in cDC (especially CD8α−CD4+) development (Esashi et al., 2008Esashi E. Wang Y.H. Perng O. Liu Y.J. Watowich S.S. Immunity. 2008; 28 (this issue): 509-520Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, Shortman and Naik, 2007Shortman K. Naik S.H. Nat. Rev. Immunol. 2007; 7: 19-30Crossref PubMed Scopus (923) Google Scholar, Zenke and Hieronymus, 2006Zenke M. Hieronymus T. Trends Immunol. 2006; 27: 140-145Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). Thus, a picture of STAT-regulated DC development from hematopoietic progenitors under the influence of either Flt3-ligand or GM-CSF emerges: In Flt3-signaling-mediated steady-state pDC and cDC development, STAT3 activation is a nonredundant requirement, whereas STAT5 is dispensable; in GM-CSF-signaling-mediated cDC development, STAT3 is dispensable and activated STAT5 suppresses pDC development. However, in the absence of STAT5, pDCs develop in GM-CSF stimulated cultures, possibly via GM-CSF-mediated STAT3 activation. Interestingly, GM-CSF-stimulated STAT5-deficient progenitors seem to produce fewer cDCs; thus it is possible that beyond suppression of pDC development, STAT5 is also directly involved in GM-CSF-mediated cDC development, an issue that needs further clarification. Furthermore, STAT3 overexpression and activation, i.e., strong Flt3-downstream signaling, seems to favor pDC over cDC development (Onai et al., 2006Onai N. Obata-Onai A. Tussiwand R. Lanzavecchia A. Manz M.G. J. Exp. Med. 2006; 203: 227-238Crossref PubMed Scopus (127) Google Scholar). Data from the above mentioned studies (Laouar et al., 2003Laouar Y. Welte T. Fu X.Y. Flavell R.A. Immunity. 2003; 19: 903-912Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, Onai et al., 2006Onai N. Obata-Onai A. Tussiwand R. Lanzavecchia A. Manz M.G. J. Exp. Med. 2006; 203: 227-238Crossref PubMed Scopus (127) Google Scholar; Esashi et al., 2008Esashi E. Wang Y.H. Perng O. Liu Y.J. Watowich S.S. Immunity. 2008; 28 (this issue): 509-520Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar) are summarized in Figure 1. What are the implications of differential cytokine- and downstream STAT-regulated DC development in vivo, and specifically, in which situation is cDC development at cost of pDC development biologically beneficial? Whereas respective receptor expression is relatively restricted to hematopoietic cells, Flt3 ligand is broadly expressed in steady state by multiple tissue stromal cells and by activated T cells; GM-CSF is produced by some stromal cells as well as activated T and NK cells, and macrophages; and main sources of M-CSF include stromal cells and endothelial cells, as well as macrophages. All three cytokine amounts increase in serum upon systemic inflammation, for example in some infections or autoimmune diseases, and upon hematopoietic challenge, such as irradiation-induced cytopenia. Less is known, however, on local cytokine amounts in a dynamically changing environment. Thus, in contrast to controlled in vitro situations in which cytokines effects are studied under exclusive and probably saturating conditions, DC progenitors in vivo are exposed to subtle gradient changes that, once a threshold is reached, will probably shape their differentiation fate. The study published here provides an exciting step forward in envisioning the in vivo situation and, as also suggested by the authors, might guide in developing therapeutic approaches, for example to diseases in which pDC excess is of pathogenetic relevance. The Signal Transducer STAT5 Inhibits Plasmacytoid Dendritic Cell Development by Suppressing Transcription Factor IRF8Esashi et al.ImmunityApril 11, 2008In BriefThe development of distinct dendritic cell (DC) subsets is regulated by cytokines. The ligand for the FMS-like tyrosine kinase 3 receptor (Flt3L) is necessary for plasmacytoid DC (pDC) and conventional DC (cDC) maturation. The cytokine GM-CSF inhibits Flt3L-driven pDC production while promoting cDC growth. We show that GM-CSF selectively utilized its signal transducer STAT5 to block Flt3L-dependent pDC development from the lineage-negative, Flt3+ (lin− Flt3+) bone-marrow subset. The signaling molecule STAT3, by contrast, was necessary for expansion of DC progenitors but not pDC maturation. Full-Text PDF Open Archive
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