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IL-7 Induces Myelopoiesis and Erythropoiesis Francesca B

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IL-7 Induces Myelopoiesis and Erythropoiesis Francesca B IL-7 Induces Myelopoiesis and Erythropoiesis Francesca B. Aiello, Jonathan R. Keller, Kimberly D. Klarmann, Glenn Dranoff, Renata Mazzucchelli and Scott K. Durum This information is current as of September 23, 2021. J Immunol 2007; 178:1553-1563; ; doi: 10.4049/jimmunol.178.3.1553 http://www.jimmunol.org/content/178/3/1553 Downloaded from References This article cites 89 articles, 40 of which you can access for free at: http://www.jimmunol.org/content/178/3/1553.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 23, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IL-7 Induces Myelopoiesis and Erythropoiesis1 Francesca B. Aiello,*† Jonathan R. Keller,‡ Kimberly D. Klarmann,‡ Glenn Dranoff,§ Renata Mazzucchelli,* and Scott K. Durum2* IL-7 administration to mice was previously reported to increase the mobilization of progenitor cells from marrow to peripheral sites. We now report that IL-7 increases the number of mature myeloid and monocytic cells in spleen and peripheral blood. This effect required T cells, and we show that IL-7 treatment in vivo induced GM-CSF and IL-3 production by T cells with memory phenotype. However, additional myelopoietic cytokines were shown to be involved because mice deficient in both GM-CSF and IL-3 also responded to IL-7 with increased myelopoiesis. Candidate cytokines included IFN-␥ and Flt3 ligand, which were also produced in response to IL-7. Because IFN-␥-deficient mice also increased myelopoiesis, it was suggested that IL-7 induced production of redundant myelopoietic cytokines. In support of this hypothesis, we found that the supernatant from IL-7-treated, purified T cells contained myelopoietic activity that required a combination of Abs against GM-CSF, IL-3, and anti-Flt3 ligand to achieve maximum neutralization. IL-7 administration increased the number of splenic erythroid cells in either normal, Rag1 Downloaded from or GM-CSF-IL-3-deficient mice, suggesting that IL-7 might directly act on erythroid progenitors. In support of this theory, we detected a percentage of TER-119؉ erythroid cells that expressed the IL-7R␣-chain and common ␥-chain. Bone marrow cells expressing IL-7R and B220 generated erythroid colonies in vitro in response to IL-7, erythropoietin, and stem cell factor. This study demonstrates that IL-7 can promote nonlymphoid hemopoiesis and production of cytokines active in the host defense system in vivo, supporting its possible clinical utility. The Journal of Immunology, 2007, 178: 1553–1563. http://www.jimmunol.org/ nterleukin-7 plays a central role in lymphopoiesis. It is es- duced by the CSF (14). IL-7R is expressed on LinϪScaIlow lym- sential for T cell development: mutations in IL-7, IL-7R ␣,or phoid progenitors, which did not show myeloid differentiation po- I common ␥-chains, or in the receptor-associated kinase Jak3 tential (15). However, there is now evidence that myeloid potential result in a dramatic block in T cell development in the thymus can persist in T and B cell lineages even after they have diverged (1–4). IL-7 is also required for T cell survival after leaving the (16–18). B/myeloid progenitors have been identified in adult bone thymus (5–10). IL-7 induces proliferation of murine B cell pro- marrow (19–21), and, interestingly, it has been suggested that dif- genitors (11), and, in combination with Flt3 ligand (Flt3-L),3 it is ferentiation is influenced by CSF present in the microenvironment indispensable for B cell development in mice (12). (22, 23). Recently, B220ϩ cells with myeloid potential responsive by guest on September 23, 2021 IL-7 is then considered primarily as a growth and antiapoptotic to IL-7 have been identified (23). IL-7 has been shown to increase factor for lymphocytes, and has a potential clinical use for the mobilization of long-term reconstituting hemopoietic progenitors treatment of immunodeficiencies. Whether IL-7 has important ef- to peripheral organs in normal and irradiated mice (24–26). It was fects on nonlymphoid cells is less explored. The aim of this study not shown whether mature myeloid cells developed in response to was to investigate the effects of IL-7 on nonlymphoid cells in vivo. IL-7, and it has also not been determined whether the effects on IL-7 deletion does not affect the development of nonlymphoid he- hemopoietic cells are direct effects of IL-7 or secondary to other mopoietic lineages (13). However, there are a few reports which induced cytokines. suggest that exogenously administered IL-7 can elicit other hemo- We report in this study that administration of IL-7 to mice in- poietic effects. In vitro, in combination with a number of CSF, IL-7 creased the numbers of myeloid, monocytic, and erythroid cells in was shown to increase the number of colonies formed by primitive the spleen, and increased numbers of neutrophils and monocytes in murine hemopoietic progenitors (LinϪScaϩ), but it was ineffective peripheral blood. Because primitive myeloid progenitors, as well when used alone, and it did not affect myeloid differentiation in- as mature myeloid cells do not express IL-7R (27–29), we inves- tigated whether some of these effects could be due to cytokines produced in vivo in response to IL-7. *Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, MD 21702; †Department of Oncology and Neuroscience, University of Chieti, Chieti, The nonlymphoid effects of IL-7 may have clinical relevance Italy; ‡Cancer and Developmental Biology Laboratory, SAIC-Frederick, National when IL-7 is given to patients, with the aim of promoting lym- § Cancer Institute-Frederick, MD 21702; and Dana Farber Cancer Institute, Boston, phocyte survival as proposed, for example, in the treatment of MA 02115 AIDS, transfer of tumor-reactive T cells, and reconstitution of T Received for publication November 17, 2005. Accepted for publication November 17, 2006. cells following bone marrow transplantation (30). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Materials and Methods Mice 1 This work was supported by the Intramural Research Program of the National In- stitutes of Health, National Cancer Institute, Center for Cancer Research. C57BL/6 (B6) mice were obtained from the Animal Production Facility of 2 Address correspondence and reprint requests to Dr. Scott K. Durum, Section of the National Cancer Institute-Frederick Cancer Research and Development Cytokines and Immunity, National Cancer Institute, Building 560, Room 31-56, Fred- Center (Frederick, MD). Rag1-deficient mice, B6 background IFN-␥-defi- erick, MD 21702. E-mail address: [email protected] cient mice, and common ␥-chain-deficient mice were obtained from The 3 Abbreviations used in this paper: Flt3-L, ligand; rhu, human recombinant; HPRT, Jackson Laboratory. GM-CSF-IL-3-deficient mice were backcrossed onto hypoxanthine phosphoribosyltransferase; F, forward; R, reverse; SCF, stem cell fac- the B6 background as previously described (31) and maintained in our tor; EPO, erythropoietin; int, intermediate; BFU, burst-forming unit; sup, supernatant. facility. Animal care was provided in accordance with procedures outlined www.jimmunol.org 1554 INDUCTION OF MYELOPOIESIS AND ERYTHROPOIESIS BY IL-7 Table I. Spleen cell subpopulations in B6 mice after treatment with and cells were washed with PBS and filtered through a nylon mesh to IL-7 in vivo obtain a single-cell suspension. Bone marrow cells were flushed from fe- murs and tibias, and after removal of red cells they were washed with PBS and filtered through a nylon mesh. Lymph node cells were obtained by Treatment mechanical dissociation, and cells were washed with PBS and filtered ϩ Vehicle IL-7 through a nylon mesh to obtain a single-cell suspension. CD3 lymph node cells were then obtained by negative selection using mouse T cell enrich- Cell Populations Cell number (ϫ10Ϫ6)a ment column (R&D Systems) in accordance with the manufacturer’s rec- ommendations, yielding Ͼ90% CD3ϩ by cytofluorometry. Lymph node ϩ cells were also fractionated into four populations by cell sorting according ءB220 b 37.3 Ϯ 6.0 179.9 Ϯ 29.8 ϩ ϩ .to the level of CD44 expression: negative, dull, intermediate, and bright ءB220 IgM b 24.5 Ϯ 3.2 129.9 Ϯ 24.5 ϩ -For Ab staining, cells in PBS/0.5% BSA were preincubated with anti ءCD3 b 31.0 Ϯ 2.8 64.3 Ϯ 6.1 ϩ Fc␥III/II receptor-blocking Ab (BD Pharmingen) for 15 min at 4°C, and ءGr-1 b 6.0 Ϯ 0.6 27.7 Ϯ 3.1 ϩ then stained with PE-conjugated anti-CD44 mAb or with a PE-conjugated ءMac-1 b 2.3 Ϯ 0.5 8.1 Ϯ 1.8 ϩ isotype-matched mAb (BD Pharmingen) as control for nonspecific staining ءTER-119 c 3.6 Ϯ 0.8 26.6 Ϯ 9.8 at 4°C for 25 min.
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