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Reprint of: Environments of B cell development夽 Motokazu Tsuneto a , Ekaterina Kajikhina a , Katharina Seiler a , Andreas Reimer a , Julia Tornack a , Corinne Bouquet a , Szandor Simmons a , Marko Knoll a , Ingrid Wolf a , Koji Tokoyoda b , Anja Hauser b , Takahiro Hara c , Shizue Tani-ichi c , Koichi Ikuta c , Joachim R. Grün b , Andreas Grützkau b , Niklas Engels e , Jürgen Wienands e , Yuki Yanagisawa d , Kazuo Ohnishi d , Fritz Melchers a,∗ a
Max Planck Institute for Infection Biology, Lymphocyte Development Group, Berlin, Germany German Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, Germany c Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan d Department of Immunology, National Institutes of Infectious Diseases, Tokyo, Japan e Cellular and Molecular Immunology, University of Göttingen, Germany b
a r t i c l e
i n f o
Article history: Available online xxx Keywords: Fetal liver B cell development Endothelial cells Mesenchymal cells
a b s t r a c t B lymphocyte development in the mouse begins with the generation of long-term reconstituting, pluripotent hematopoietic stem cells, over multipotent myeloid/lymphoid progenitors and common lymphoid progenitors to B-lineage committed pro/pre B and pre B cells, which first express pre B cell receptors and then immunoglobulins, B cell receptors, to generate the repertoires of peripheral B cells. This development is influenced and guided by cells of non-hematopoietic and hematopoietic origins. We review here some of the recent developments, and our contributions in this fascinating field of developmental immunology. © 2013 Elsevier B.V. All rights reserved.
1. Origins and lineages of B lymphocytes Hematopoietic cell development in the mouse begins with the establishment of blood circulation in the mouse embryo at embryonic day (E) 7.5 in yolk sac, i.e. extra-embryonically [1], and generates fetal globin-expressing erythrocytes, megakaryocytes, platelets and a special lineage of unusually long-lived myeloid cells [2,3], but no lymphocytes. This first wave of so-called “primitive” hematopoiesis is succeeded by a second wave of (now “definitive”) hematopoiesis, which generates erythrocytes expressing adulttype globin, megakaryocytes, platelets, short-lived myeloid cells, as well as lymphoid cells from hematopoietic progenitor cells that originate from the aorta/gonad/mesonephros area of the developing embryo [4–9]. B-lymphoid cells and myeloid cells develop from E12.5 in one wave mainly in fetal liver [10], while T lymphoid cell development,
DOI of original article: http://dx.doi.org/10.1016/j.imlet.2013.11.011. 夽 This article is a reprint of a previously published article. For citation purposes, please use the original publication details: Immunol. Lett. 157(1–2), pp. 60–63. ∗ Corresponding author at: Max Planck Institute for Infection Biology, Lymphocyte Development Group, Charitéplatz 1, D-10117 Berlin, Germany. Tel.: +49 30 28460260. E-mail addresses: [email protected], [email protected] (F. Melchers).
again from E12.5 onwards, is restricted to the fetal thymus [11,12]. From E13.5 bone development generates an environment in marrow that allows definitive hematopoiesis, and, therefore, Blymphocyte development not only in one wave, but as a continuous regenerative process from pluripotent hematopoietic stem cells (pHSCs) throughout life. This might be a property of bone marrow not developed in fetal thymus that appear to establish conditions in the endosteum allowing the long-term retention of pHSC in specialized niches [13–16]. The expression of miR221 [17] could favor the homing and retention of such LT-pHSCs in hypoxic niches [18] of bone marrow. The developmental pattern of the localization of pHSC in the embryo between E10.5 and E11.5 indicates that pHSCs are mainly found inside the embryonic blood vessel, and are attracted to vascular endothelium in cell clusters [19]. Since, at that time, pHSCs are found in embryonic blood of fetal liver, as they are thereafter from E15.5 in bone marrow, but not in fetal thymus, this vascular endothelium might be differentially attractive for pHSC, high in the developing fetal liver and, later, bone marrow, and low in thymus. 2. Development of hematopoiesis and of B lymphocytes from embryonic stem cells “in vitro” The stage of embryonic mesoderm development at E8.5 to hemangioblasts, i.e. progenitors of vascular muscle, vascular
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Fig. 1. First wave of embryonic B cell development from embryonic stem cells to lymphopoiesis in fetal liver to mature B1a cells in the peripheral lymphoid sites. Embryonic stem cells (ESCs) from blastocysts or, less efficiently, induced pluripotent stem cells (iPSCs) developed from pluripotent hematopoietic stem cells (pHSCs) or from pre BI cells can develop “in vitro” to hematopoietic cell lineages, including sIgM + B cells. However, long-term resting pHSC with long-term repopulation capacities (LT-pHSC) only develop “in vivo”, and only in embryonic blood, and during adulthood in bone marrow. Multipotent myeloid/lymphoid progenitors (MPP) and IL7-receptor + common lymphoid progenitors (CLP) enter the developing fetal liver through LYVE-1 + vascular endothelium, attracted by CXCL10, and migrate, attracted by CXCl10 and CXCL12, produced by mesenchymally derived ALCAM + liver cells to these second non-hematopoietic sites producing IL7. IL7 then induces the proliferation and differentiation of CD19 + surrogate L chain + pre BI cells to pre B cell receptor + pre II cells, immature sIgM + B cells, before they leave the liver to become mature IgM + B1a cells populating peripheral sites such as the peritoneum. For further details see the text.
endothelium and hematopoietic cells [20] can be developed “in vitro” by the differentiation of embryonic stem cells (ESC), and becomes detectable as flk1 + tie2 + progenitor cells [21–24]. Differential gene expression analyses of differentiating ESCs between days 5 and 6 detect genes that are known to control primitive and definitive hematopoiesis, among them the genes encoding the transcription factors Tal1 and Runx1 [25–28]. Deficiency in the gene encoding the transcription factor Tal1 has been found to lead to defective primitive and definitive hematopoiesis, while RUNX1deficiency allows primitive, but not definitive hematopoiesis and B-lymphopoiesis. Runx-1 is a direct target of Tal-1 [29]. However, pHSCs retain long-term repopulating activity and multipotency in the absence of stem cell leukemia SCL/tal-1 gene [30], as SCL/Tal-1 is essential for hematopoietic commitment of the hemangioblasts but not for its development [31]. In experiments employing the “in vitro” capacities of ESCs for hematopoietic development we have recently found that Tal1 expression is needed, and only needed, to express Runx1 in mesoderm [32]. Hence, ectopic, retrovirally transduced expression of Runx1 in differentiating mesoderm-like Tal1−/− ESCs was found to be sufficient to induce primitive as well as definitive hematopoiesis in the absence of Tal1. From these results it might be expected that a microenvironment interacting with hemangioblasts to develop pHSCs influences the expression of Runx1. However, until today “in vitro” pHSC development has not generated a long-term (LT-) repopulating cell compartment from differentiating ESCs [23].
3. Development of B lymphocytes in fetal liver LT-pHSCs are induced – probably through an autocrine, inductive influence of FLT3-L with its receptor flt3 [33,34] – in one wave in fetal liver and thymus of the developing embryo, and later in bone marrow and adult thymus as a continuous production of cells to differentiate first to short-term (ST) repopulating pHSCs and, thereafter, to multipotent myeloid/lymphoid progenitors (MPP). MPPs begin to express a series of chemokine receptors that are expected to be involved in their chemo-attraction to microenvironments of cells, which produce the corresponding chemokines to attract the MPPs to the sites of further myeloid or lymphoid development. Thus, MPPs are also expected to express cytokine receptors that can induce their differentiation at the site of cytokine production – for myeloid cell development M-CSF, acting on the M-CSF receptor c-fms, for lymphoid cell development IL7, acting on the IL7 receptor. We have studied these early interactions for early B cell development in fetal liver [35]. The FACS analysis of non-hematopoietic (CD45- TER 119- ) cells at E13.5 to 15.5 detected two major subpopulations: VCAM-1+ CD105++ LYVE-1++ endothelial cells, and VCAM-1+CD105low ALCAM++ mesenchymally derived liver cells. A striking change was detected between E13.5 and later days of development (E14.5 to E16.5) by histochemical analyses of sections of fetal liver in the localization of B-lymphoid c-kit+ IL7R␣+ . At E13.5 three of the 4 such B-progenitors, then CD19-surrogate L
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chain (SLC)-negative, IgH- and L chain-locus non-rearranged, were found in contact with endothelial cells, and less than 3 of the 100 of them near mesenchymal liver cells. One day later, and thereafter also at E15.5 and E16.5, half to three quarters of these progenitors, now SLC+ , DH JH -rearranged and increasingly CD19+ , were found in contact with mesenchymally derived liver cells, while less than 5 of the 100 cells remained near endothelial cells. The endothelial cells were found to produce only the chemokine CXCL10, but not CXCL12, and also did not produce either IL7 or M-CSF. On the other hand, the mesenchymally derived cells produced CXCL10, CXCL12, M-CSF, and (all of them) IL7. The receptors for the two chemokines, CXCR3 and CXCR4, were expressed on the IL7R␣+ progenitors. In “in vitro” chemo-attraction assays the E13.5 B-progenitors migrated in response to both CXCL10 and CXCL12, while the E15.5 B-progenitors had lost their migration capacity toward CXCL10, but remained sensitive to CXCL12. From these results we have proposed a model for the development of early stages of B cell development to B1a-type B lineage cells in fetal liver that is shown in Fig. 1. It proposes that B-progenitors enter the developing fetal liver at E13.5 from vascular endothelium, attracted by CXCL10, then transmigrate within a day to move to mesenchymal liver cells, attracted by CXCL10 and CXCL12. In this second microenvironment, the progenitors differentiate, induced by locally produced IL7, to pro/pre B cells, become insensitive to CXCL10, but remain sensitive to, and attracted by CXCL12. Within the next two days the pro/pre B and pre BI cells expand by proliferation, before they begin VH to DH JH -rearrangements to express pre B cell receptors, the first step in the development of IgH- and L chain-expressing B lymphocytes [36,37]. The emerging repertoires of lymphocytes with unique antigenspecific receptors are then screened for autoreactivity. Those lymphocytes with receptors recognizing auto-antigens with high avidities are negatively selected, i.e. deleted by apoptosis. These phases of repertoire development and selection are expected to be controlled by cell-intrinsic signal transductions and regulations of gene expression programs. Extrinsically, they should, again, be influenced by specialized microenvironments that provide chemokines, cell–cell contacts and cytokines for the development of the lymphoid-lineage cells in their development through these phases.
Acknowledgements The work of the Lymphocyte Development Group was supported by Max Planck Institutional support to the Max Planck Fellowship of F.M., and by a Kosellek Grant of the DFG to F.M. (ME-2764-2-1).
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[32] Tornack J, Seiler K, Grützkau A, Grün JR, Onodera M, Melchers F, et al. Ectopic Runx1 expression rescues Tal-1-deficiency in the generation of primitive and definitive hematopoiesis. PLoS ONE 2013;8(July (7)):e70116, http://dx.doi.org/10.1371/journal.pone.0070116 [Print 2013]. [33] Adolfsson J, Borge OJ, Bryder D, Theilgaard-Mönch K, Astrand-Grundström I, Sitnicka E, et al. Upregulation of Flt3 expression within the bone marrow Lin(−)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of selfrenewal capacity. Immunity 2001;15(October (4)):659–69. [34] Sitnicka E, Bryder D, Theilgaard-Mönch K, Buza-Vidas N, Adolfsson J, Jacobsen SE. Key role of flt3 ligand in regulation of the common lymphoid progenitor but not in maintenance of the hematopoietic stem cell pool. Immunity 2002;17(October (4)):463–72.
[35] Tsuneto M, Tokoyoda K, Kajikhina E, Hauser AE, Hara T, Tani-Ichi S, et al. Cell progenitors and precursors change their microenvironment in fetal liver during early development. Stem Cells 2013, http://dx.doi.org/10.1002/stem.1421. [36] Melchers F. The pre-B-cell receptor: selector of fitting immunoglobulin heavy chains for the B-cell repertoire. Nat Rev Immunol 2005;5(January (7)):578–84 [Review]. [37] Knoll M, Yanagisawa Y, Simmons S, Engels N, Wienands J, Melchers F, et al. The non-Ig parts of the VpreB and 5 proteins of the surrogate light chain play opposite roles in the surface representation of the precursor B cell receptor. J Immunol 2012;188(June (12)):6010–7, http://dx.doi.org/10.4049/ jimmunol.1200071.
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ARTICLE IN PRESS
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Immunology Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
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Review
Reprint of: Environments of B cell development夽 Motokazu Tsuneto a , Ekaterina Kajikhina a , Katharina Seiler a , Andreas Reimer a , Julia Tornack a , Corinne Bouquet a , Szandor Simmons a , Marko Knoll a , Ingrid Wolf a , Koji Tokoyoda b , Anja Hauser b , Takahiro Hara c , Shizue Tani-ichi c , Koichi Ikuta c , Joachim R. Grün b , Andreas Grützkau b , Niklas Engels e , Jürgen Wienands e , Yuki Yanagisawa d , Kazuo Ohnishi d , Fritz Melchers a,∗ a
Max Planck Institute for Infection Biology, Lymphocyte Development Group, Berlin, Germany German Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, Germany c Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan d Department of Immunology, National Institutes of Infectious Diseases, Tokyo, Japan e Cellular and Molecular Immunology, University of Göttingen, Germany b
a r t i c l e
i n f o
Article history: Available online xxx Keywords: Fetal liver B cell development Endothelial cells Mesenchymal cells
a b s t r a c t B lymphocyte development in the mouse begins with the generation of long-term reconstituting, pluripotent hematopoietic stem cells, over multipotent myeloid/lymphoid progenitors and common lymphoid progenitors to B-lineage committed pro/pre B and pre B cells, which first express pre B cell receptors and then immunoglobulins, B cell receptors, to generate the repertoires of peripheral B cells. This development is influenced and guided by cells of non-hematopoietic and hematopoietic origins. We review here some of the recent developments, and our contributions in this fascinating field of developmental immunology. © 2013 Elsevier B.V. All rights reserved.
1. Origins and lineages of B lymphocytes Hematopoietic cell development in the mouse begins with the establishment of blood circulation in the mouse embryo at embryonic day (E) 7.5 in yolk sac, i.e. extra-embryonically [1], and generates fetal globin-expressing erythrocytes, megakaryocytes, platelets and a special lineage of unusually long-lived myeloid cells [2,3], but no lymphocytes. This first wave of so-called “primitive” hematopoiesis is succeeded by a second wave of (now “definitive”) hematopoiesis, which generates erythrocytes expressing adulttype globin, megakaryocytes, platelets, short-lived myeloid cells, as well as lymphoid cells from hematopoietic progenitor cells that originate from the aorta/gonad/mesonephros area of the developing embryo [4–9]. B-lymphoid cells and myeloid cells develop from E12.5 in one wave mainly in fetal liver [10], while T lymphoid cell development,
DOI of original article: http://dx.doi.org/10.1016/j.imlet.2013.11.011. 夽 This article is a reprint of a previously published article. For citation purposes, please use the original publication details: Immunol. Lett. 157(1–2), pp. 60–63. ∗ Corresponding author at: Max Planck Institute for Infection Biology, Lymphocyte Development Group, Charitéplatz 1, D-10117 Berlin, Germany. Tel.: +49 30 28460260. E-mail addresses: [email protected], [email protected] (F. Melchers).
again from E12.5 onwards, is restricted to the fetal thymus [11,12]. From E13.5 bone development generates an environment in marrow that allows definitive hematopoiesis, and, therefore, Blymphocyte development not only in one wave, but as a continuous regenerative process from pluripotent hematopoietic stem cells (pHSCs) throughout life. This might be a property of bone marrow not developed in fetal thymus that appear to establish conditions in the endosteum allowing the long-term retention of pHSC in specialized niches [13–16]. The expression of miR221 [17] could favor the homing and retention of such LT-pHSCs in hypoxic niches [18] of bone marrow. The developmental pattern of the localization of pHSC in the embryo between E10.5 and E11.5 indicates that pHSCs are mainly found inside the embryonic blood vessel, and are attracted to vascular endothelium in cell clusters [19]. Since, at that time, pHSCs are found in embryonic blood of fetal liver, as they are thereafter from E15.5 in bone marrow, but not in fetal thymus, this vascular endothelium might be differentially attractive for pHSC, high in the developing fetal liver and, later, bone marrow, and low in thymus. 2. Development of hematopoiesis and of B lymphocytes from embryonic stem cells “in vitro” The stage of embryonic mesoderm development at E8.5 to hemangioblasts, i.e. progenitors of vascular muscle, vascular
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Fig. 1. First wave of embryonic B cell development from embryonic stem cells to lymphopoiesis in fetal liver to mature B1a cells in the peripheral lymphoid sites. Embryonic stem cells (ESCs) from blastocysts or, less efficiently, induced pluripotent stem cells (iPSCs) developed from pluripotent hematopoietic stem cells (pHSCs) or from pre BI cells can develop “in vitro” to hematopoietic cell lineages, including sIgM + B cells. However, long-term resting pHSC with long-term repopulation capacities (LT-pHSC) only develop “in vivo”, and only in embryonic blood, and during adulthood in bone marrow. Multipotent myeloid/lymphoid progenitors (MPP) and IL7-receptor + common lymphoid progenitors (CLP) enter the developing fetal liver through LYVE-1 + vascular endothelium, attracted by CXCL10, and migrate, attracted by CXCl10 and CXCL12, produced by mesenchymally derived ALCAM + liver cells to these second non-hematopoietic sites producing IL7. IL7 then induces the proliferation and differentiation of CD19 + surrogate L chain + pre BI cells to pre B cell receptor + pre II cells, immature sIgM + B cells, before they leave the liver to become mature IgM + B1a cells populating peripheral sites such as the peritoneum. For further details see the text.
endothelium and hematopoietic cells [20] can be developed “in vitro” by the differentiation of embryonic stem cells (ESC), and becomes detectable as flk1 + tie2 + progenitor cells [21–24]. Differential gene expression analyses of differentiating ESCs between days 5 and 6 detect genes that are known to control primitive and definitive hematopoiesis, among them the genes encoding the transcription factors Tal1 and Runx1 [25–28]. Deficiency in the gene encoding the transcription factor Tal1 has been found to lead to defective primitive and definitive hematopoiesis, while RUNX1deficiency allows primitive, but not definitive hematopoiesis and B-lymphopoiesis. Runx-1 is a direct target of Tal-1 [29]. However, pHSCs retain long-term repopulating activity and multipotency in the absence of stem cell leukemia SCL/tal-1 gene [30], as SCL/Tal-1 is essential for hematopoietic commitment of the hemangioblasts but not for its development [31]. In experiments employing the “in vitro” capacities of ESCs for hematopoietic development we have recently found that Tal1 expression is needed, and only needed, to express Runx1 in mesoderm [32]. Hence, ectopic, retrovirally transduced expression of Runx1 in differentiating mesoderm-like Tal1−/− ESCs was found to be sufficient to induce primitive as well as definitive hematopoiesis in the absence of Tal1. From these results it might be expected that a microenvironment interacting with hemangioblasts to develop pHSCs influences the expression of Runx1. However, until today “in vitro” pHSC development has not generated a long-term (LT-) repopulating cell compartment from differentiating ESCs [23].
3. Development of B lymphocytes in fetal liver LT-pHSCs are induced – probably through an autocrine, inductive influence of FLT3-L with its receptor flt3 [33,34] – in one wave in fetal liver and thymus of the developing embryo, and later in bone marrow and adult thymus as a continuous production of cells to differentiate first to short-term (ST) repopulating pHSCs and, thereafter, to multipotent myeloid/lymphoid progenitors (MPP). MPPs begin to express a series of chemokine receptors that are expected to be involved in their chemo-attraction to microenvironments of cells, which produce the corresponding chemokines to attract the MPPs to the sites of further myeloid or lymphoid development. Thus, MPPs are also expected to express cytokine receptors that can induce their differentiation at the site of cytokine production – for myeloid cell development M-CSF, acting on the M-CSF receptor c-fms, for lymphoid cell development IL7, acting on the IL7 receptor. We have studied these early interactions for early B cell development in fetal liver [35]. The FACS analysis of non-hematopoietic (CD45- TER 119- ) cells at E13.5 to 15.5 detected two major subpopulations: VCAM-1+ CD105++ LYVE-1++ endothelial cells, and VCAM-1+CD105low ALCAM++ mesenchymally derived liver cells. A striking change was detected between E13.5 and later days of development (E14.5 to E16.5) by histochemical analyses of sections of fetal liver in the localization of B-lymphoid c-kit+ IL7R␣+ . At E13.5 three of the 4 such B-progenitors, then CD19-surrogate L
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chain (SLC)-negative, IgH- and L chain-locus non-rearranged, were found in contact with endothelial cells, and less than 3 of the 100 of them near mesenchymal liver cells. One day later, and thereafter also at E15.5 and E16.5, half to three quarters of these progenitors, now SLC+ , DH JH -rearranged and increasingly CD19+ , were found in contact with mesenchymally derived liver cells, while less than 5 of the 100 cells remained near endothelial cells. The endothelial cells were found to produce only the chemokine CXCL10, but not CXCL12, and also did not produce either IL7 or M-CSF. On the other hand, the mesenchymally derived cells produced CXCL10, CXCL12, M-CSF, and (all of them) IL7. The receptors for the two chemokines, CXCR3 and CXCR4, were expressed on the IL7R␣+ progenitors. In “in vitro” chemo-attraction assays the E13.5 B-progenitors migrated in response to both CXCL10 and CXCL12, while the E15.5 B-progenitors had lost their migration capacity toward CXCL10, but remained sensitive to CXCL12. From these results we have proposed a model for the development of early stages of B cell development to B1a-type B lineage cells in fetal liver that is shown in Fig. 1. It proposes that B-progenitors enter the developing fetal liver at E13.5 from vascular endothelium, attracted by CXCL10, then transmigrate within a day to move to mesenchymal liver cells, attracted by CXCL10 and CXCL12. In this second microenvironment, the progenitors differentiate, induced by locally produced IL7, to pro/pre B cells, become insensitive to CXCL10, but remain sensitive to, and attracted by CXCL12. Within the next two days the pro/pre B and pre BI cells expand by proliferation, before they begin VH to DH JH -rearrangements to express pre B cell receptors, the first step in the development of IgH- and L chain-expressing B lymphocytes [36,37]. The emerging repertoires of lymphocytes with unique antigenspecific receptors are then screened for autoreactivity. Those lymphocytes with receptors recognizing auto-antigens with high avidities are negatively selected, i.e. deleted by apoptosis. These phases of repertoire development and selection are expected to be controlled by cell-intrinsic signal transductions and regulations of gene expression programs. Extrinsically, they should, again, be influenced by specialized microenvironments that provide chemokines, cell–cell contacts and cytokines for the development of the lymphoid-lineage cells in their development through these phases.
Acknowledgements The work of the Lymphocyte Development Group was supported by Max Planck Institutional support to the Max Planck Fellowship of F.M., and by a Kosellek Grant of the DFG to F.M. (ME-2764-2-1).
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