Ординатура / Офтальмология / Английские материалы / Antigen Presenting Cells and the Eye_Zierhut, Rammensee, Streilein_2007
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Contributors
Michael G. Anderson Department of Molecular Physiology and Biology, University of Iowa, Iowa City, Iowa, U.S.A.
Thomas Bieber Department of Dermatology, University of Bonn,
Bonn, Germany
Serge Camelo School of Anatomy and Human Biology, University of Western Australia, Crawley, Western Australia, Australia
Reza Dana Laboratory of Corneal Immunology, Schepens Eye Research Institute, Cornea Service, Massachusetts Eye and Ear Infirmary, and Department of Ophthalmology, Harvard University, Boston, Massachusetts, U.S.A.
Magdalena Baladud de Saint Jean Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A.
Andrew Dick Bristol Eye Hospital, Bristol, U.K.
Chuanqing Ding Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A.
Alexander H. Enk Department of Dermatology, University of Heidelberg, Heidelberg, Germany
John V. Forrester Institute of Medical Sciences, University of Aberdeen, Foresterhill, U.K.
A. Paiman Ghafoori Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, U.S.A.
Gregory S. Hageman Department of Ophthalmology and Visual Science, University of Iowa, Iowa City, Iowa, U.S.A.
Linda D. Hazlett Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, U.S.A.
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Robert L. Hendricks Department of Ophthalmology, Immunology, and Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
Kristin Jäger Department of Anatomy and Cell Biology, Martin-Luther- University of Halle-Wittenberg, Halle, Germany
Martine J. Jager Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
Simon W. M. John The Jackson Laboratory, Howard Hughes Medical Institute, Bar Harbor, Maine, U.S.A.
Tero Kivelä Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland
Audrey H. Lau Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
Janet Liversidge Institute of Medical Sciences, University of Aberdeen, Foresterhill, U.K.
Manfred B. Lutz Institute for Virology and Immunobiology, University of Wuerzburg, Wuerzburg, Germany
Karsten Mahnke Department of Dermatology, University of Heidelberg,
Heidelberg, Germany
Teemu Mäkitie Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland
Markus G. Manz Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
Bita Manzouri Department of Ocular Immunology, Institute of Ophthalmology, University College London, London, U.K.
Sharmila Masli Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, U.S.A.
Paul G. McMenamin School of Anatomy and Human Biology, University of Western Australia, Crawley, Western Australia, Australia
Austin K. Mircheff Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A.
Robert F. Mullins Department of Ophthalmology and Visual Science, University of Iowa, Iowa City, Iowa, U.S.A.
Jerry Y. Niederkorn Departments of Ophthalmology and Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.
Contributors |
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Natalija Novak Department of Dermatology, University of Bonn,
Bonn, Germany
Masaharu Ohbayashi Emory Eye Center, School of Medicine, Emory University, Atlanta, Georgia, U.S.A.
Santa Jeremy Ono Emory Eye Center, School of Medicine, Emory University, Atlanta, Georgia, U.S.A.
Fiedrich Paulsen Department of Anatomy and Cell Biology, Martin-Luther-University of Halle-Wittenberg, Halle, Germany
Hans-Georg Rammensee Departments of Cell Biology and Immunology, University of Tübingen, Tübingen, Germany
Joel E. Schechter Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A.
Saadettin Sel Department of Ophthalmology, Martin-Luther-University
of Halle-Wittenberg, Halle, Germany
Joan Stein-Streilein Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, U.S.A.
Philipp Steven Department of Ophthalmology, UK-SH, Campus Lübeck,
Lübeck, Germany
J. Wayne Streilein† Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, U.S.A.
Angus W. Thomson Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
Patrick Tighe Department of Immunology, Queens Medical Center,
Nottingham, U.K.
Päivi Toivonen Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland
Yanru Wang Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A.
Season Yeung School of Anatomy and Human Biology, University of Western Australia, Crawley, Western Australia, Australia
†Deceased.
1
Dendritic Cell and Natural
Type I Interferon-Producing
Cell Development
Markus G. Manz
Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
INTRODUCTION
The differentiation of hematopoietic stem cells (HSCs) to mature cells is a lineal process, characterized by a stepwise loss of self-renewal capacity, and by final restriction to one mature cell type. HSCs, as well as developmental intermediates with limited cellular expansion potential and restriction to specific mature cell lineages, were isolated to high purity (for review, see 1,2). Consecutively, a phenotypic and functional defined hematopoetic developmental tree has been suggested: Long-term HSCs (LTHSCs) give rise to short-term HSCs (ST-HSCs), which generate non–self-renewing, multi-potent progenitors (MPPs), which further develop to either clonal common lymphoid progenitors (CLPs) and subsequently to pro T cells or pro B cells, or to clonal common myeloid progenitors (CMPs) and subsequently to granulocyte/macrophage progenitors (GMPs) or megakaryocyte/erythrocyte progenitors (MEPs), all of which have been defined in both mice and humans (3–9). Those progenitors each have potent proliferative potential, generating plenty of progeny; however, they do not self-renew, and offspring cells are only generated in a single burst.
DENDRITIC CELL AND TYPE I INTERFERON-PRODUCING CELL DEVELOPMENT
Dendritic cells (DCs) as well as natural type I interferon-producing cells (IPCs, also called plasmacytoid dendritic cells, PDCs) are relatively recently described
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cells of the hematopoietic system (1). With the exception of Langerhans cells (LCs) (10) and possibly some other non-lymphatic tissue DCs, most DCs and IPCs have a short in vivo turnover time of maximally two weeks (11,12). Thus, these cells need to be regenerated continuously from HSCs, a process that must be tightly regulated. Multiple DC types, differing in phenotype, localization, and function, were identified over the last few decades (13,14). With the recent phenotypic and functional identification of IPCs in both humans (15–17) and mice (18–20), and the finding that these cells are capable of differentiating to DCs, the heterogeneous group of DCs was further enlarged (21). Over the last few years we and others were able to elucidate some of the developmental pathways of these rare cells. Most of these findings are summarized in recent reviews (e.g., 14,21–24). Thus, I focus on our findings on DC and IPC development from mouse bone marrow or human cord-blood earlyprogenitor cells.
Regarding DC development, two opposing models were suggested: a “specialized lineage” model, where different DC subtypes are determined at the level of early hematopoietic progenitors and thus belong to different hematopoietic lineages; and a “environmental instruction” model, where different DC subtypes belong to the same hematopoietic lineage and, upon local influences, are determined at the level of an immediate DC precursor. The notion of specialized DC lineages was supported by several studies in mice and men: first, it was shown that mouse thymocyte progenitors are capable of producing CD8a-expressing DCs in vivo, a DC population that constitutes most DCs in mouse thymus and about 30% of DCs in secondary lymphoid organs. Thus, a T-cell-associated CD8α “lymphoid” DC lineage was suggested (25,26), a concept that seemed to be further enhanced by the findings that these cells do not need granulocyte– macrophage colony-stimulating factor (GM-CSF) for DC differentiation in vitro (27), and that several transcription factor deficient mice lack only CD8α negative DCs (28–30). Second, human (and later also mouse) IPCs were suggested to be of lymphoid lineage origin because human IPCs express CD2, high CD4, CD5, and CD7, but not CD11c, CD13, and CD33 (15,21), because they express T- and B-cell development-associated mRNA transcripts (31–34), and because GM-CSF does not promote their development (35,36). However, although these observations added significantly to the understanding of critical cytokines and transcription factors for DC and IPC development, the conclusions on lineage associations remained indirect.
To more directly test DC and IPC lineage associations, developmental capacities from each above-mentioned lineage restricted progenitor populations were tested in vitro and in vivo. We and others came to several unexpected findings: (i) mouse CLPs, as well as CMPs, generate CD8α positive and CD8α negative DCs in vivo (37–39); (ii) DC differentiation activity is preserved in early T-cell progenitors, declining along T-cell maturation, as well as in GMPs (38,39); (iii) irrespective of the progenitor transplanted, we preferentially found development of CD8α positive DCs in lethally irradiated animals (37,38); (iv) the
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classical DC and IPC developmental capacity of progenitors is overlapping (40– 42); (v) if DC and IPC reconstitution capacities of progenitors reflect in vivo, steady-state DC and IPC development, most secondary-tissue DCs and IPCs are of myeloid origin, while myeloid and lymphoid progenitors reconstitute about half of thymus DCs and IPCs each, respectively (37,38,40,42); (vi) definitive B- cell or MEP commitment terminates both DC and IPC developmental capacities (38,40); (vii) finally, human myeloid and lymphoid progenitors show similar DC and IPC developmental capacities as mouse progenitors (43). Taken together, these experiments uncovered an unexpected redundancy in DC and IPC development from both lymphoid and myeloid progenitor cell populations.
We thus were interested in determining what might define the capacity of these progenitors to receive and execute signals that drive DC and IPC development. We and others looked at the flt3-receptor/flt3-ligand, a nonredundant cytokine receptor/ligand pair in DC and IPC development. Flt3-ligand knockout mice and mice with hematopoietic system restricted Stat3 deletions show massively reduced DCs and IPCs (44,45); flt3-ligand injection or over-expression of flt3ligand increases DCs and IPCs in mice and men (19,46–53); moreover, flt3-ligand is capable of driving in vitro differentiation of both human and mouse DCs and IPCs (35,43,54). The receptor for flt3-ligand, flt3, was shown to be expressed on ST-reconstituting HSCs in mice (55,56). We further evaluated expression of flt3 along the hematopoietic tree. Flt3 is transiently upregulated from ST-HSCs on most common lymphoid and myeloid progenitors, but is downregulated in definitive B-cell, T-cell, and MEP lineage commitment (49); while flt3 is not expressed on other steady-state hematopoietic cell lineages, it is expressed by lymphoid tissue DCs and IPCs (49). Furthermore, both lymphoid and myeloid offspring DCs are increased in flt3-ligand injected animals (49). Thus, DC and IPC development is confined to flt3 expressing hematopoietic progenitor cells, and flt3ligand drives DC and IPC development along both pathways (41,49).
CONCLUSION
We thus further tested whether flt3 would be capable of delivering an instructive signal for DC and IPC development. Indeed, over-expression of flt3 in flt3 negative progenitors rescues DC and IPC development to levels of flt3 positive progenitors. This process involves upregulation of DCand GM-development affiliated genes (57). These findings suggest that flt3 signal strength might regulate DC and IPC development. We therefore propose a steady-state “flt3-license pathway” for DC and IPC development, where differentiation of these cells from flt3 positive progenitors is possible as long as no competing signal shuts it down. It is important to stress that this model might only reflect the situation in steady state. During inflammatory stress, GM-CSF, IL-4, and TNF-α likely become important cytokines that guide monocytes and macrophages to differentiate to DCs. Indeed, in vivo DC development from mouse monocytes was not observed in steady state, but only upon inflammation (58–60). Taken together, the
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flt3-pathway would be dominant in steady state, while the GM-CSF-pathway might be a major pathway upon inflammation.
ACKNOWLEDGMENT
The author thanks members of the laboratory for their contribution to this work, and the Deutsche Krebshilfe, the Deutsche Forschungsgemeinschaft, and the Swiss National Science Foundation for grant support.
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