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Proliferation by 2B4/CD48 Interactions T Cell Cutting Edge: Regulation of CD8+ T Cell Proliferation by 2B4/CD48 Interactions Taku Kambayashi, Erika Assarsson, Benedict J. Chambers and Hans-Gustaf Ljunggren This information is current as of September 29, 2021. J Immunol 2001; 167:6706-6710; ; doi: 10.4049/jimmunol.167.12.6706 http://www.jimmunol.org/content/167/12/6706 Downloaded from References This article cites 23 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/167/12/6706.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 29, 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 © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. ● Cutting Edge: Regulation of CD8؉ T Cell Proliferation by 2B4/CD48 Interactions1 Taku Kambayashi,2* Erika Assarsson,2* Benedict J. Chambers,* and Hans-Gustaf Ljunggren3*† To date, the only known 2B4-binding molecule is CD48. Bind- The biological function of 2B4, a CD48-binding molecule ex- ing studies have shown that CD48 has a 5–10 times stronger af- pressed on T cells with an activation/memory phenotype, is not finity for 2B4 than for CD2 (7, 8). Anti-CD48 Abs have been clear. In this report, we demonstrate that proliferation of found to inhibit activation of CD4ϩ and CD8ϩ T cells (9, 10). ؉ Ϫ Ϫ CD8 T cells is regulated by 2B4. Proliferative responses of Whereas CD2 / mice are phenotypically similar to wild-type Downloaded from ؉ CD8 T cells were significantly reduced by anti-2B4 Ab. The mice (11), T cells from CD48Ϫ/Ϫ mice show a severe reduction in effects were not potentiated by anti-CD48 Ab, suggesting that proliferation and IL-2 production in response to lectins, anti-CD3 the observed responses were driven by 2B4/CD48 interactions. Ab, and alloantigen (8, 12). The relatively normal phenotype of the Surprisingly, the 2B4/CD48-dependent proliferative responses CD2Ϫ/Ϫ mice suggests that CD48-binding ligands other than CD2 were also observed in the absence of APCs. This suggests that may compensate for the absence of CD2. 2B4/CD48 interactions can occur directly between T cells. Fur- In this report, we demonstrate that 2B4 is associated with an http://www.jimmunol.org/ ϩ thermore, when activated 2B4؉CD8؉ T cells were mixed with activation/memory phenotype of CD8 T cells. Furthermore, the 2B4؊CD8؉ TCR-transgenic T cells and specific peptide-loaded results suggest that 2B4 on activated/memory T cells serves as a APC, the proliferation of the latter T cells was inhibited by ligand for CD48, and by its ability to interact with CD48 provides anti-2B4 Ab. Taken together, this suggests that 2B4 on acti- costimulatory-like function for neighboring T cells. vated/memory T cells serves as a ligand for CD48, and by its ability to interact with CD48 provides costimulatory-like func- Materials and Methods tion for neighboring T cells. The Journal of Immunology, Mice Adult C57BL/6 (B6) and TCR-transgenic (Tg)4 (F ) mice specific for an 2001, 167: 6706–6710. 5 by guest on September 29, 2021 influenza nucleoprotein epitope, ASNENMDAM, presented on H-2Db (13) were bred at the Microbiology and Tumor Biology Center, Karolinska he 2B4 molecule (CD244) is expressed on NK cells, Institutet (Stockholm, Sweden). Animal care was in accordance with na- ϩ tional and institutional guidelines. monocytes, and basophils, and on subsets of TCR␥␦ T T cells and CD8ϩ T cells (1–4). Most of the information Reagents available on 2B4 comes from studies of NK cells. Cross-linking of All chemicals were purchased from Sigma-Aldrich (St. Louis, MO) unless 2B4 on IL-2-activated NK cells leads to stimulation of lytic ac- otherwise specified. The influenza virus nucleoprotein-derived peptide (nu- ␥ tivity (1, 4, 5), IFN- secretion (1), and granule exocytosis (6). The cleoprotein (NP)366–374), ASNENMDAM, was purchased from Research biological function of 2B4 on CD8ϩ T cells remains largely un- Genetics (Huntsville, AL). All Ab used were purchased from BD PharM- clear. 2B4ϩCD8ϩ T cells have been associated with non-MHC- ingen (San Diego, CA) except for anti-CD2 (Southern Biotechnology As- sociates, Birmingham, AL). restricted cytotoxicity (6), but cross-linking of 2B4 on CD8ϩ T ϩ cells does not trigger redirected lysis of FcR-expressing targets, Preparation of CD8 T cells cytokine production, or proliferation (4). CD8␣ϩ cells were purified from spleens of mice using the MACS sepa- ration system (Miltenyi Biotec, Bergisch Gladbach, Germany) according to the manufacturer’s guidelines and resuspended in complete medium (␣MEM, 10 mM HEPES, 2 ϫ 10Ϫ5 M 2-ME, 10% FCS, 100 U/ml pen- icillin, 100 U/ml streptomycin; Life Technologies, Paisley, U.K.) plus re- *Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden; † combinant human IL-2 (1000 U/ml; PeproTech, Rocky Hill, NJ) for 6 days. and Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, ϩ ϩ Huddinge University Hospital, Stockholm, Sweden FACS analysis of these cells demonstrated that only CD8 TCR cells were present in these cultures. Purification of CD8ϩ T cells from influenza- Received for publication June 1, 2001. Accepted for publication October 25, 2001. infected mice has been described previously (14). 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 RT-PCR with 18 U.S.C. Section 1734 solely to indicate this fact. ϩ 1 2B4 transcripts were detected using RNA from naive or activated CD8 T This work was supported by the Swedish Foundation of Strategic Research, the cells by RT-PCR using the following primers: 2B4 short transcripts were Karolinska Institutet, the Swedish Medical Research Council, the Swedish Cancer Ј Ј Society, the Tobias Foundation, the Åke Wiberg Foundation, the Alex and Eva Wall- detected using 5 -ACTGTTTTTGTCCTGCTTGGTG and 3 -AGGAAAC stro¨m Foundation, and the Lars Hiertas Foundation. TGGTGGAGAAGAAAA (Cybergene, Stockholm, Sweden) encompass- ing nt 573-1093 of murine 2B4 (m2B4) short. m2B4 long transcripts were 2 T.K. and E.A. contributed equally to this study. 3 Address correspondence and reprint requests to Dr. Hans-Gustaf Ljunggren, Micro- biology and Tumor Biology Center, Karolinska Institutet, 171 77 Stockholm, Sweden. 4 Abbreviations used in this paper: Tg, transgenic; DC, dendritic cell; LAT cell, E-mail address: [email protected] lymphokine-activated T cell; NP, nucleoprotein; m2B4, murine 2B4. Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 ● The Journal of Immunology 6707 detected using 5Ј-TGGAAGAAGACAGAACAGGG and 3Ј-TGGAAT their cytoplasmic tails while having identical extracellular domains CAGAAGGCTTGCAC encompassing nt 283-1136 of m2B4 long. cDNA (18, 19). As shown in Fig. 1B, both the short and long forms of ␤ quality was confirmed by amplification of a -actin gene fragment. 2B4 were equally up-regulated in CD8ϩ T cells after stimulation Flow cytometry with IL-2. Taken together, the data indicated that expression of 2B4 was increased in IL-2-activated CD8ϩ T cells both at the cell Following FcR-block, cells were stained with the specified Ab or its iso- b surface and at the transcriptional level. 2B4 expression was also type control or D -NP366-RED670 tetramer (14, 15). The fluorescence in- ϩ tensity was measured on a FACScan flow cytometer (BD Biosciences, observed on CD8 T cells on day 10 post-influenza infection (peak ϩ Mountain View, CA) and analyzed using CellQuest computer software of infection). Five to 10% of all CD8 T cells in the lungs of (BD Biosciences). infected mice expressed 2B4 compared with 1–2% in untreated CD8ϩ T cell proliferation assays mice (Fig. 1C). The expression of 2B4 on virus-specific T cells was confirmed using tetramers of MHC class I molecules refolded Bone marrow-derived dendritic cells (DC) were pulsed with ASNEN b 4 with an influenza nucleoprotein epitope (D -NP366) (Fig. 1C). Al- MDAM peptide overnight at 37°C and seeded at 2 ϫ 10 cells/well in Ϫ ϫ 4 ϩ though 2B4 was observed also on tetramer T cells, this could be U-bottom 96-well plates. A total of 3 10 TCR-Tg CD8 T cells (naive ϩ ϩ or IL-2-activated) or TCR-Tg lymphokine-activated T (LAT) cells (FACS related to the other CD8 2B4 T cells recognizing other flu sorted into NK1.1ϩ or NK1.1Ϫ) were added to each well with the indicated epitopes, or bystander activation, or both. azide-free Ab. When B6 LAT cells were mixed with naive TCR-Tg CD8ϩ T cells, 4 ϫ 104 B6 LAT cells (sorted into NK1.1ϩ or NK1.1Ϫ) were added 2B4/CD48 interactions are involved in Ag-specific and cytokine- with 3 ϫ 104 naive TCR-Tg CD8ϩ T cells to each well. In APC-free induced proliferation of preactivated CD8ϩ T cells b experiments, plates were coated overnight at 4°C with purified D -NP366 ϩ monomers (14, 15) at various concentrations with anti-CD28 Ab (10 ␮g/ The effect of anti-2B4 Ab on the proliferation of CD8 T cells was Downloaded from ϩ ml) in PBS.
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