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And Maintenance of Peripheral T Cells Locus Controls IL-7 Receptor An Enhancer of the IL-7 Receptor α-Chain Locus Controls IL-7 Receptor Expression and Maintenance of Peripheral T Cells This information is current as Akifumi Abe, Shizue Tani-ichi, Soichiro Shitara, Guangwei of October 2, 2021. Cui, Hisataka Yamada, Hitoshi Miyachi, Satsuki Kitano, Takahiro Hara, Ryo Abe, Yasunobu Yoshikai and Koichi Ikuta J Immunol 2015; 195:3129-3138; Prepublished online 2 September 2015; doi: 10.4049/jimmunol.1302447 Downloaded from http://www.jimmunol.org/content/195/7/3129 Supplementary http://www.jimmunol.org/content/suppl/2015/09/01/jimmunol.130244 http://www.jimmunol.org/ Material 7.DCSupplemental References This article cites 46 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/195/7/3129.full#ref-list-1 Why The JI? Submit online. by guest on October 2, 2021 • 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 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 © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology An Enhancer of the IL-7 Receptor a-Chain Locus Controls IL-7 Receptor Expression and Maintenance of Peripheral T Cells Akifumi Abe,*,† Shizue Tani-ichi,* Soichiro Shitara,*,† Guangwei Cui,*,‡ Hisataka Yamada,x Hitoshi Miyachi,{ Satsuki Kitano,{ Takahiro Hara,* Ryo Abe,‖ Yasunobu Yoshikai,x and Koichi Ikuta* The IL-7R plays critical roles in lymphocyte development and homeostasis. Although IL-7R expression is strictly regulated during lymphocyte differentiation and the immune response, little is known regarding its in vivo regulation. To address this issue, we established a mouse line with targeted deletion of the conserved non-coding sequence 1 (CNS1) element found 3.6 kb upstream of the IL-7Ra promoter. We report that IL-7Ra isexpressednormallyonTandBcellsinthymusandbonemarrowofCNS12/2 mice Downloaded from except for in regulatory T cells. In contrast, these mice show reduced IL-7Ra expression in conventional CD4 and CD8 T cells as well as regulatory T, NKT, and gd T cells in the periphery. CD4 T cells of CNS12/2 mice showed IL-7Ra upregulation in the absence of growth factors and IL-7Ra downregulation by IL-7 or TCR stimulation, although the expression levels were lower than those in control mice. Naive CD4 and CD8 T cells of CNS12/2 mice show attenuated survival by culture with IL-7 and reduced homeostatic proliferation after transfer into lymphopenic hosts. CNS12/2 mice exhibit impaired maintenance of Ag-stimulated T cells. Furthermore, IL-7Ra upregulation by glucocorticoids and TNF-a was abrogated in CNS12/2 mice. This work demon- http://www.jimmunol.org/ strates that the CNS1 element controls IL-7Ra expression and maintenance of peripheral T cells, suggesting differential regu- lation of IL-7Ra expression between central and peripheral lymphoid organs. The Journal of Immunology, 2015, 195: 3129–3138. nterleukin-7, a cytokine essential for lymphocyte develop- IL-7 supports survival and homeostasis of naive and memory ment and homeostasis, controls the survival, proliferation, and T cells (6). IL-7 exerts its effects through interaction with the IL-7R, I differentiation of early T and B cells (1–3) as well as V(D)J which consists of the IL-7R a-chain (IL-7Ra) and a common cy- recombination of the TCRg and IgH loci (4, 5). In the periphery, tokine receptor g-chain. IL-7Ra also dimerizes with the thymic stromal lymphopoietin receptor. IL-7 binding to the IL-7R activates by guest on October 2, 2021 JAK-1 and JAK-3, which then activates STAT5 and PI3K. *Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; †Graduate School of Bio- IL-7Ra expression is dynamically controlled in T and B cell studies, Kyoto University, Kyoto 606-8501, Japan; ‡Graduate School of Medicine, development. During T cell differentiation, IL-7Ra is expressed Kyoto University, Kyoto 606-8501, Japan; xDivision of Host Defense, Network Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka in double-negative (DN) thymocytes, downregulated in double- 812-8582, Japan; {Reproductive Engineering Team, Institute for Virus Research, Kyoto positive (DP) thymocytes, upregulated in single-positive (SP) ‖ University, Kyoto 606-8507, Japan; and Division of Immunobiology, Research Insti- thymocytes, and maintained in naive T cells in the periphery (2, tute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan 7). When naive T cells receive Ag stimuli, the IL-7Ra is down- Received for publication September 12, 2013. Accepted for publication July 28, 2015. regulated in effector T cells (6, 8, 9). However, a small subset of effector T cells, referred to as memory precursor effector cells, This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Scientific Research [C] Grants 25460589 upregulates IL-7Ra and differentiates into memory CD8 T cells [to K.I.] and 26460572 [to S.T.], Scientific Research on Innovative Areas Grants (9). During B cell development, IL-7Ra is expressed on common 25111504 and 15H01153 [to K.I.], and Young Scientists [B] Grants 24790469 [to S.T.] and 24790468 [to T.H.]). This work was also supported by the Platform Project lymphoid progenitors (CLPs) and pro– and pre–B cells and then is for Supporting Drug Discovery and Life Science Research (Platform for Dynamic downregulated during the transition from pre–B to B cells (7, 10, 11). Approaches to Living System) from the Ministry of Education, Culture, Sports, Thus, IL-7Ra expression is precisely regulated during lymphocyte Science and Technology of Japan, a grant from the Fujiwara Memorial Foundation, a grant from the Shimizu Foundation for Immunology and Neuroscience, and by the development and the immune response. BioLegend/TOMY Digital Biology Young Scientist Research Award for 2011. IL-7Ra expression on T cells is regulated at transcriptional Address correspondence and reprint requests to Dr. Koichi Ikuta, Laboratory of levels and suppressed by IL-7 and other prosurvival cytokines, Biological Protection, Department of Biological Responses, Institute for Virus Re- such as IL-2, IL-4, IL-6, and IL-15 (12). Additionally, TCR sig- search, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail address: [email protected] naling also represses IL-7Ra transcription (13). Furthermore, both The online version of this article contains supplemental material. glucocorticoids (GC) and TNF-a upregulate IL-7Ra transcription (14–16). Additionally, several transcriptional factors interact with Abbreviations used in this article: cDC, conventional dendritic cell; CLP, common lymphoid progenitor; CNS1, conserved non-coding sequence 1; DN, CD42CD82 the IL-7Ra locus and control its transcription. Two Ets family double-negative; DP, CD4+CD8+ double-positive; ES, embryonic stem; GC, gluco- proteins, PU.1 and GA binding protein a, interact with the IL-7Ra corticoid; GR, glucocorticoid receptor; IEL, intraepithelial lymphocyte; ab IEL, TCRb+ intraepithelial lymphocyte; IHL, intrahepatic lymphocyte; IL-7Ra, IL-7R promoter and are crucial for IL-7Ra transcription in early B and a-chain; pDC, plasmacytoid dendritic cell; rLM-OVA, recombinant Listeria mono- T cells, respectively (17, 18). We previously showed that a con- + + 2 + 2 + cytogenes expressing OVA; SP, CD3 CD4 CD8 or CD3 CD4 CD8 single-posi- served non-coding sequence 1 (CNS1) element found 3.6 kb up- tive; Treg, Foxp3+CD4+ regulatory T cell. stream of the IL-7Ra promoter is a GC-responsive enhancer of the Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 IL-7Ra locus in vitro (16). Consistently, a DNase I hypersensitivity www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302447 3130 FUNCTION OF AN IL-7 RECEPTOR LOCUS ENHANCER site was identified 3.8 kb upstream of that promoter (19). Consensus BioLegend (San Diego, CA), and Wako Pure Chemical Industries: CD3ε motifs for NF-kB, the GC receptor (GR), Evi-1, and forkhead (145-2C11), TCRb (H57-597), CD4 (RM4.5), CD8a (53-6.7), CD8b transcription factors are conserved in the CNS1 element, and Foxo1 (H35-17.2), CD25 (7D4), Foxp3 (FJK-165), CD44 (IM7), gdTCR (GL3), NK1.1 (PK136), CD45R/B220 (RA3-6B2), CD43 (S7), BP-1 (6C3), CD24 and Foxp1 interact with the element to control IL-7Ra expression in (30F1), Igm (M41), CD11c (N418), CD11b (M1/70), Gr-1 (RB6-8C5), naive T and early B cells (20–22). However, it is largely unknown TER-119, Sca-1 (E13-161.7), c-Kit (2B8), Thy-1 (53-2.1), IL-7Ra how the element controls IL-7Ra expression during lymphocyte (A7R34), CD45.1 (A20), CD45.2 (104), Ly-6C (HK1.4), IFN-g (XMG1.2), 694 development and the immune response. phosphorylated STAT5 (Tyr ) (47), Bcl-2 (A19-3), annexin V, Ki-67 (SolA15). H-2Kb OVA G4 tetramer–SIIGFEKL-PE was purchased from To determine its function in vivo, we established a mouse line Medical and Biological Laboratories (Nagoya, Japan). Biotinylated mAbs carrying targeted deletion of the CNS1 element and analyzed IL-7Ra were detected with PE-, allophycocyanin-, or PE-Cy7–conjugated streptavidin expression at different differentiation stages. IL-7Ra expression (eBioscience). Viable cells were analyzed with FACSCalibur or FACSCanto was significantly reduced in peripheral T cells of CNS12/2 mice, II flow cytometers (BD Biosciences) with CellQuest and FlowJo software.
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