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A Novel Functional T Cell Hybridoma Recognizes Macrophage Cell A Novel Functional T Cell Hybridoma Recognizes Macrophage Cell Death Induced by Bacteria: A Possible Role for Innate Lymphocytes in Bacterial Infection This information is current as of October 1, 2021. Koichi Kubota J Immunol 2006; 176:7576-7588; ; doi: 10.4049/jimmunol.176.12.7576 http://www.jimmunol.org/content/176/12/7576 Downloaded from References This article cites 50 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/176/12/7576.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on October 1, 2021 *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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology A Novel Functional T Cell Hybridoma Recognizes Macrophage Cell Death Induced by Bacteria: A Possible Role for Innate Lymphocytes in Bacterial Infection Koichi Kubota1 We have established a novel TCR␣␤ (TCRV␤6)؉CD4؊CD8؊ T cell hybridoma designated B6HO3. When the B6HO3 cells were cocultured with bacterial-infected J774 macrophage-like cells, IFN-␥ production by B6HO3 cells was triggered through direct cell-cell contact with dying J774 cells infected with Listeria monocytogenes (LM), Shigella flexneri,orSalmonella typhimurium that expressed the type III secretion system, but not with intact J774 cells infected with heat-killed LM, nonhemolytic lysteriolysin ␥-O-deficient (Hly؊) LM, plasmid-cured Shigella, or stationary-phase Salmonella. However, the triggering of B6HO3 cells for IFN production involved neither dying hepatoma cells infected with LM nor dying J774 cells caused by gliotoxin treatment or freeze d d d thawing. Cycloheximide and Abs to H-2K , H-2D ,Ia , CD1d, TCRV␤6, and IL-12 did not inhibit the contact-dependent IFN-␥ Downloaded from response, indicating that this IFN-␥ response did not require de novo protein synthesis in bacterial-infected J774 cells and was TCR and IL-12 independent. Thus, in an as yet undefined way, B6HO3 hybridoma recognizes a specialized form of macrophage cell death resulting from bacterial infection and consequently produces IFN-␥. Moreover, contact-dependent interaction of minor subsets of splenic ␣␤ T cells, including NKT cells with dying LM-infected J774 and bone marrow-derived macrophage (BMM) cells, proved to provide an IFN-␥-productive stimulus for these minor T cell populations, to which the parental T cell of the B6HO3 hybridoma appeared to belong. Unexpectedly, subsets of ␥␦ T and NK cells similarly responded to dying LM-infected macrophage http://www.jimmunol.org/ cells. These results propose that innate lymphocytes may possess a recognition system sensing macrophage cell “danger” resulting from bacterial infection. The Journal of Immunology, 2006, 176: 7576–7588. acrophages are well known for their scavenger func- survive and replicate inside macrophages (12–15). In addition, a tion. They are able to ingest and digest a variety of variety of bacterial pathogens are known to induce cell death in M particulate bodies, such as macromolecular com- macrophages (15–26). However, the biological significance of the plexes, aged erythrocytes, apoptotic cells, and microbial pathogens pathogen-induced cell death in macrophages is not fully defined (1). Upon infection, in addition to ingesting microbial pathogens, with respect to the host-parasite relationship and it may differ with by guest on October 1, 2021 macrophages recognize pathogen-associated molecular patterns of individual pathogens; viz, the macrophage cell death may be one bacteria, such as LPS or bacterial CpG DNA, via pattern recogni- evasion mechanisms of bacteria from killing by macrophages, or it tion receptors that include several members of the TLR family (2), may constitute a host defense response to the incoming pathogen and consequently produce a variety of soluble mediators, such as to halt its survival within macrophages and/or to present Ags to the cytokines and chemokines that recruit immune cells and induce adaptive immune system through bystander dendritic cells (27, inflammation (1). Among other things, IL-12 produced by macro- 28), or it may be the result of a bacterial strategy to promote dis- phages (3), in conjunction with other cytokines like IL-18 (4), ease through activation of caspase-1 which can cleave the pro- induces NK cells (5, 6) and some TCR␣␤-bearing memory-type forms of the inflammatory cytokines IL-1␤ and IL-18 (18–20). ϩ CD8 T cells (7–9) to produce IFN-␥, which in turn activates In previous studies, we developed a novel T cell hybridization macrophages to ultimately kill internalized bacteria via generation system, referred to as a functional T cell hybridoma, which com- of reactive nitrogen and oxygen intermediates (10). The macro- prised production of growth-arrested hybrids between the YACUT phages, therefore, constitute both sentinels and the first line of T cell lymphoma (29) and normal T cells and subsequent sponta- defense against bacterial pathogens, and IFN-␥ is the most impor- neous cell transformation of the hybrids (30, 31). Compared with tant key factor of early host resistance against bacterial infection. the ordinary T cell hybridomas using the BW5147 T cell lym- Microbes, on the other hand, have evolved a variety of coun- phoma (32), our hybridoma system is unique in that the hybrid- termeasures to macrophage defense mechanisms (1, 11). Intracel- omas dictate most of the terminally differentiated phenotypes of lular bacterial pathogens evade the macrophage killing mecha- normal parental T cells, thus preserving the effector functions of T nisms that eliminate intracellular pathogens, and thus they can lymphocytes, such as T cell contact helper activity (30) and cyto- toxic activity (31). Thus, we were interested in the feasibility of constructing functional T cell hybridomas with hitherto unknown Department of Microbiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan phenotypes by using this hybridization system (32), as T lympho- Received for publication November 16, 2005. Accepted for publication March cytes were becoming recognized as consisting of functionally 29, 2006. more heterogeneous populations than previously anticipated (33– The costs of publication of this article were defrayed in part by the payment of page 36). In a series of attempts to produce functional T cell hybridomas charges. This article must therefore be hereby marked advertisement in accordance derived from minor T cell populations, we obtained a novel T cell with 18 U.S.C. Section 1734 solely to indicate this fact. hybridoma designated B6HO3. We focused in this study on the 1 Address correspondence and reprint requests to Dr. Koichi Kubota, Department of Microbiology, Kitasato University School of Medicine, 1-15-1 Kitazato, Sagamihara, characterization of this hybridoma and found that the B6HO3 T Kanagawa 228, Japan. E-mail address: [email protected] cell hybridoma recognizes and responds to a specialized form of Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 The Journal of Immunology 7577 cell death in bacterial-infected J774 macrophage cells with the Iad mAbs were purchased from Meiji Institute of Health Science. Fab of production of IFN-␥, a crucial cytokine for microbicidal functions anti-V␤6 mAb was produced by Takara Bio. PE-conjugated streptavidin of macrophages. This finding predicted that a minor subset of T was purchased form DakoCytomation. Gliotoxin and cycloheximide (CHX) were purchase from Sigma-Aldrich. cells should have the ability to recognize cell death in macro- phages resulting from bacterial infection. In fact, we have shown Cell fusion and hybrid selection ␣␤ in this study that not only minor subsets of spleen T cells but ϫ 6 ϫ 6 ␥␦ ␥ YC11 cells (10 10 ) were hybridized with 10 10 secondary C3H/He also subsets of T and NK cells produce IFN- in response to anti-DBA/2 MLC cells as described previously with slight modifications direct cell-cell contact with dying Listeria monocytogenes (LM)2- (31). Briefly, after fusion, cells were suspended in culture medium (DMEM Ϫ infected macrophage cells. Thus, this study suggests that the innate supplemented with 10% FCS, 10 mM HEPES, 5 ϫ 10 5 M 2-ME, and 1 immunity may involve a lymphocyte recognition system sensing mM nonessential amino acids) containing hypoxanthine/aminopterin/thy- midine, distributed into the wells of a 24-well microculture plate and cul- macrophage cell “danger” resulting from bacterial infection. tured for 18 days to eliminate unhybridized YC11 cells. Eighteen days after fusion, unhybridized MLC cells were eliminated by the panning method as Materials and Methods described previously (30). The adherent cells on the panning plate were ϫ 6 Mice and cell lines recovered by vigorous pipetting with culture medium, mixed with 6 10 irradiated DBA/2 mouse spleen
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