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3156.Full.Pdf A New IFN-Like Cytokine, Limitin Modulates the Immune Response Without Influencing Thymocyte Development This information is current as Isao Takahashi, Hiroshi Kosaka, Kenji Oritani, William R. of October 1, 2021. Heath, Jun Ishikawa, Yu Okajima, Megumu Ogawa, Sin-ichiro Kawamoto, Masahide Yamada, Hiroaki Azukizawa, Satoshi Itami, Kunihiko Yoshikawa, Yoshiaki Tomiyama and Yuji Matsuzawa J Immunol 2001; 167:3156-3163; ; doi: 10.4049/jimmunol.167.6.3156 Downloaded from http://www.jimmunol.org/content/167/6/3156 References This article cites 68 articles, 28 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/167/6/3156.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • 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 © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. A New IFN-Like Cytokine, Limitin Modulates the Immune Response Without Influencing Thymocyte Development1 Isao Takahashi,* Hiroshi Kosaka,† Kenji Oritani,2* William R. Heath,‡ Jun Ishikawa,* Yu Okajima,* Megumu Ogawa,* Sin-ichiro Kawamoto,* Masahide Yamada,* Hiroaki Azukizawa,† Satoshi Itami,† Kunihiko Yoshikawa,† Yoshiaki Tomiyama,* and Yuji Matsuzawa* A novel IFN-like molecule, limitin, was recently identified and revealed to suppress B lymphopoiesis through the IFN-␣␤ receptor, although it lacked growth suppression on myeloid and erythroid progenitors. Here we have studied diverse effects of limitin on T lymphocytes and compared limitin with previously known IFNs. Like IFN–␣ and -␤, limitin modified immunity in the following responses. It suppressed mitogen- and Ag-induced T cell proliferation through inhibiting the responsiveness to exogenous IL-2 rather than suppressing the production of IL-2. In contrast, limitin enhanced cytotoxic T lymphocyte activity associated with the Downloaded from perforin-granzyme pathway. To evaluate the effect of limitin in vivo, a lethal graft-versus-host disease assay was established. Limitin-treatment of host mice resulted in the enhancement of graft-versus-host disease. Limitin did not influence thymocyte development either in fetal thymus organ cultures or in newborn mice injected with limitin-Ig, suggesting that limitin is distin- guishable from IFN-␣ and -␤. From these findings, it can be speculated that the human homolog of limitin may be applicable for clinical usage because of its IFN-like activities with low adverse effects on, for example, T lymphopoiesis, erythropoiesis, and myelopoiesis. The Journal of Immunology, 2001, 167: 3156–3163. http://www.jimmunol.org/ nterferon (IFN) was first discovered in 1957 as a substance ing quiescence in memory T cells at the end of immune responses that induced an antiviral state in cells (1). Since then, several (13, 14). These immunomodulatory activities have been applied to I kinds of IFNs have been identified and classified based on the many clinical uses of IFN-␣ and -␤ including the treatment of cell surface receptor, primary sequence, and chromosomal local- malignancies (15–17). ization (2). All IFNs are now placed into two groups, type I and Recently we identified a novel IFN-like cytokine, limitin, that type II IFNs. The type I IFN family is composed of IFN-␣,-␤,-␻, has ϳ30% amino acid sequence identity with IFN-␣,-␤, and -␻ and -␶ that have homology to each other, bind to the same cell (18). Limitin displays its biological functions through the IFN-␣␤ by guest on October 1, 2021 surface receptor, and show overlapping functions. Type I IFNs are receptor, implying that limitin is likely to belong to the type I IFN known for broad biological properties including anti-proliferative, family. Like IFN-␣ and -␤, limitin suppressed the proliferation of immunomodulatory, and antiviral effects (3, 4). In the immune- pre-B cells in response to IL-7 and completely blocked the pro- surveillance system, T cells stimulated with Ag-MHC and co- duction of B lymphocytes in Whitlock-witte type long-term bone stimulatory signals proliferate and differentiate into effector cells marrow cultures (18). Moreover, administration of limitin to new- with a wide range of functions (5, 6). Type I IFNs can modulate born mice resulted in the reduction of B lineage cell populations in these responses by inhibiting T cell proliferation (7, 8), by enhanc- the bone marrow (18). In contrast with IFN-␣ and -␤, limitin did ing T and NK cell cytotoxicity (9, 10), and by enhancing the ex- not affect the responsiveness of myeloid progenitors to colony- pression of MHC class I molecules (11). Furthermore, they aug- stimulating factors or that of erythroid progenitors to erythropoi- ment the proliferation of CD44highCD8ϩ T cells and prolong their etin in vitro (18). Furthermore, treatment of newborn mice with life span in vivo (12). Activated T cells are saved from apoptosis limitin did not change the number or the proportion of CD11b- with type I IFNs and can be reactivated efficiently with IL-2, sug- positive and TER119-positive cells in bone marrow (18). Although gesting that type I IFNs are presumably important for re-establish- limitin shares the IFN-␣␤ receptor and induces expression of IFN regulatory factor-1 (IRF-1),3 it is distinct from IFN-␣ and -␤ be- cause of its failure to suppress the growth of myeloid and erythroid Departments of *Internal Medicine and Molecular Science and †Dermatology, Grad- progenitors (18). uate School of Medicine, Osaka University, Osaka, Japan; and ‡The Water and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Victoria, To investigate this structurally and functionally unique cytokine, Australia we needed to compare the effects of limitin on various cell types Received for publication February 20, 2001. Accepted for publication July 6, 2001. to that of IFN-␣ and -␤. This study was undertaken to determine The costs of publication of this article were defrayed in part by the payment of page whether limitin has any regulatory effects on T cells in vivo and in charges. This article must therefore be hereby marked advertisement in accordance vitro. We will discuss some functional differences between limitin with 18 U.S.C. Section 1734 solely to indicate this fact. and previously known IFNs. 1 This work was supported in part by grants from the Japan Leukemia Research Foundation, the Japan Research Foundation for Clinical Pharmacology, the Osaka Medical Research Foundation for Incurable Disease, the Ministry of Education, Sci- 3 Abbreviations used in this paper: IRF-1, IFN regulatory factor-1; LN, lymph node; ence, and Culture of Japan, and the Japan Society for the Promotion of Science. TRAIL, TNF-related apoptosis-inducing ligand; GVHD, graft-versus-host disease; 2 Address correspondence and reprint requests to Dr. Kenji Oritani, Department of EL-4Ab, T lymphoma cell line (EL-4) transfected with I-Ab; EL-4AbOVA, T lym- Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka Uni- phoma cell line (EL-4) transfected with I-Ab and OVA gene; limitin-Ig, fusion protein versity, 2-2 Yamada-oka, Suita City, Osaka 565-0871, Japan. E-mail address: composed of limitin and human Ig; MMC, mitomycin C; CMA, concanamycin A; [email protected] FTOC, fetal thymus organ culture; Fas L, Fas ligand. Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 The Journal of Immunology 3157 Materials and Methods Cross-linking of TCR by immobilized anti-CD3 Ab Mice The rabbit anti-Armenian hamster IgG (10 ␮g/ml) was coated onto 96-well OT-I mice are MHC class I-restricted OVA-specific TCR transgenic mice flat-bottom polystyrene tissue culture plates overnight at 4°C. After three ϩ washes with PBS, anti-CD3 Ab (145-2C11 cell culture supernatant) was having CD8 T cells (19, 20). OT-II mice are MHC class II-restricted ϩ then incubated for4hatroom temperature. The culture plate was washed OVA-specific TCR transgenic mice carrying CD4 T cells (21). II-mOVA ϫ 5 transgenic mice express the membrane-bound form of OVA under the con- in PBS three times again before use. Purified T cells (2 10 /well) were trol of MHC class II (I-E) promoter. C57BL/6 mice and BALB/c mice were cultured in the anti-CD3 Ab-coated microplate for 3 days. purchased (Japan Clea, Tokyo, Japan). All mice were maintained at the Ag-specific T cell proliferation assay Institute for Experimental Animals, Osaka University (Osaka, Japan). Mice were ϳ6–10 wk of age at the time of use. To evaluate the OVA Ag-specific proliferation of CD8ϩ cells, bulk or purified CD8ϩV␣2ϩ populations of OT-I LN cells (2 ϫ 105/well) and Culture medium and cell lines MMC-treated EL-4Ab or EL-4AbOVA cells (2 ϫ 105/well) were mixed and cultured in flat-bottom 96-well microplates. To evaluate the OVA Ag- DMEM (Nakarai Tesque, Kyoto, Japan) supplemented with 10% heat-in- specific proliferation of CD4ϩ cells, purified CD4ϩV␣2ϩ cells of OT-II activated FCS (ICN Biomedicals, Aurora, OH), 50 ␮M 2-ME, 2 mM L- mice (4 ϫ 105/well) were stimulated with 10 ␮M class II OVA peptide and glutamine, 10 mM HEPES, and antibiotics (100 U of penicillin G, 100 irradiated spleen cells from C57BL/6 mice. Triplicate cultures were set up ␮g/ml streptomycin) were used for the in vitro culture assays.
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