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Role of CD244 and SLAM-Associated B Cell Induction of IL-13 Expression

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Role of CD244 and SLAM-Associated B Cell Induction of IL-13 Expression B Cell Induction of IL-13 Expression in NK Cells: Role of CD244 and SLAM-Associated Protein This information is current as Ning Gao, Pamela Schwartzberg, Julie A. Wilder, Bruce R. of September 26, 2021. Blazar and Dorothy Yuan J Immunol 2006; 176:2758-2764; ; doi: 10.4049/jimmunol.176.5.2758 http://www.jimmunol.org/content/176/5/2758 Downloaded from References This article cites 64 articles, 44 of which you can access for free at: http://www.jimmunol.org/content/176/5/2758.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 September 26, 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 B Cell Induction of IL-13 Expression in NK Cells: Role of CD244 and SLAM-Associated Protein Ning Gao,* Pamela Schwartzberg,† Julie A. Wilder,‡ Bruce R. Blazar,§ and Dorothy Yuan1* NK cells are an important component of the innate immune system that can also interact with B cells in a mutually productive manner. We have previously shown that activated B cells can induce NK cells to up-regulate their secretion of IFN-␥. In this study, we show that B cells, and, particularly, marginal zone B cells, can, in addition, induce NK cells via direct cell-cell interactions to express mRNA encoding the Th2 cytokine IL-13. The induction of NK cell IL-13 mRNA expression requires the ligation of the CD244 receptor by the CD48 ligand on B cells via signaling pathways that depend upon expression of the X-linked lymphopro- liferative disease gene product, SH2D1A/DSHP/SAP (SLAM-associated protein, or SAP) in NK cells. Thus, the positive signals attributed to the B cell activation of CD244 on murine NK cells appears to be more similar to the activity of CD244 on human cells. The induction of IL-13 mRNA by B cells may account for the effect of NK cells on the generation of Th2-type responses in Downloaded from the presence of some adjuvants. The Journal of Immunology, 2006, 176: 2758–2764. he presence of clonally distributed receptors on B lym- induce NK cells to express IL-13 as well and might therefore ex- phocytes confer on them two important functions. They plain why NK cells can sometimes exert Th2-like effects. T can process and present Ags to T cells and, in response to Parameters of induction of IL-13 mRNA expression by NK cells appropriate stimulation, they can be induced to secrete Abs that are can be measured quite precisely because even after in vitro IL-2 http://www.jimmunol.org/ important in the control of pathological insult. In addition to these propagation NK cells do not produce measurable amounts of IL-13 Ag-specific functions, we showed previously that in vivo-preacti- mRNA. We found that, whereas highly purified resting B cells can vated B cells can up-regulate IFN-␥ production by NK cells (1) via induce NK cells to synthesize IL-13 mRNA, marginal zone (MZ) direct cell-cell interactions. Whereas it is clear that secretion of B cells are much more effective than follicular B cells. By the use IFN-␥ by NK cells plays an important role in Th1 responses, we of Abs specific for possible ligand/receptors as well as mice with have found that under some conditions of immunization, NK cells targeted disruptions of genes encoding cell surface molecules, we can also increase the IgG1 response (2) that is usually associated found that activation of NK cells by B cells requires the interaction with Th2 cytokines. Although murine NK cells have not been of CD48 and its counterreceptor, CD244 (2B4), expressed on NK shown to secrete IL-4 (3, 4), a closely related Th2 cytokine, IL-13, cells. CD244 is a member of the Ig superfamily (14), which in- by guest on September 26, 2021 can be produced by NK cells (5, 6). IL-13 shares many properties cludes other membrane-associated proteins, such as CD150 (sig- with IL-4, but also has many distinct functions. For example, IL-13 naling lymphocyte activation molecule (SLAM)2), CD2, and is more important than IL-4 in the development of airway hyper- CD48. These proteins are expressed to varying degrees in subsets reactivity and mucus secretion as well as control of some parasites of immune cells and may function as ligands or receptors. Murine (7–9). The production of a Th2 cytokine by NK cells provides CD244 has been shown to mediate both activating and inhibitory another source of cytokines for the alternative pathway of macro- signals. The results reported herein show, for the first time, that phage activation (10). The induction of T cell production of IL-13 ligation of the CD244 receptor on NK cells by CD48 expressed on may be mediated by other cytokines as well as cell surface ligands B cells results only in activation. As for human NK cells (15, 16) such as CD30L (11). NK cells can be also induced to produce this activation pathway can be shown to be mediated via the IL-13 by cytokines such as IL-2 and IL-18 (5, 12, 13), but whether SLAM-associated protein (SAP). The induction by B cells of the they can be stimulated by surface ligands expressed by other cell production of Th2 as well as Th1 cytokines by NK cells provides types is not known. Since we have shown that B cells can up- further evidence for a B cell regulatory role for NK cells in vivo. regulate NK cell IFN-␥ production, we tested whether they can Materials and Methods Cell preparations and culture *Department of Molecular Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390; †National Human Genome Research Institute, National For B cell preparations, T lymphocytes were depleted from splenocytes of Institutes of Health, Bethesda, MD 20892; ‡Lovelace Respiratory Research Institute, Ͻ ␥Ϫ/Ϫ § BALB/c-Ifg tm1 (IFN- ) (17), or C57BL/6 (both from The Jackson Albuquerque, NM 87108; and Department of Pediatrics, Division of Blood and Mar- Laboratory), or D0.11 mice (Ref. 18; provided by Dr. M. Siegelman, Uni- row Transplantation, and Cancer Center, University of Minnesota Hospital and Can- cer Center, Minneapolis, MN 55455 versity of Texas Southwestern Medical Center, Dallas, TX) mice, and frac- tionated by Percoll gradient centrifugation as previously described (19). Received for publication July 28, 2005. Accepted for publication December 28, 2005. The high-density fraction (20) was further purified by binding to CD43 The costs of publication of this article were defrayed in part by the payment of page MicroBeads (Miltenyi Biotec) to deplete remaining non-B cells. B cells charges. This article must therefore be hereby marked advertisement in accordance were found routinely to be Ͼ95% positive for the CD19 marker. For in with 18 U.S.C. Section 1734 solely to indicate this fact. vivo modulation of CD48, IFN-␥Ϫ/Ϫ mice were injected two times with 1 Address correspondence and reprint requests to Dr. Dorothy Yuan, Department of 300 ␮g/animal of an ammonium sulfate cut of anti-CD48 (HM48-1) 2 days Molecular Pathology, University of Texas Southwestern Medical Center, Dallas, TX apart (21). B cells were isolated 1 day after the last injection. NK cells were 75390. E-mail address: [email protected] purified from BALB/c IFN-␥Ϫ/Ϫ, C57BL/6, or D0.11 mice or from Ϫ/Ϫ Ϫ/Ϫ 2 Abbreviations used in this paper: SLAM, signaling lymphocyte activation molecule; CD2 (22), CD244 (23), and C.B-17 SCID mice (all bred and pro- SAP, SLAM-associated protein; QM, quasi-monoclonal; MZ, marginal zone; SH2, vided by Dr. M. Bennett, University of Texas Southwestern Medical Cen- Ϫ Ϫ Src homology 2. ter). The generation of SAP / mice has been described (24). Spleen cells Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 The Journal of Immunology 2759 from the mice were first passed over a nylon wool column to remove FACS analysis and cell sorting adherent cells, then depleted of T cells by complement-mediated lysis. NK cells were then isolated by positive selection using anti-DX5 Abs and mag- B cells isolated from QM mice were labeled with fluorescein-conju- netic beads (Miltenyi Biotec). Purified cells were cultured in 1000 U/ml gated -anti-IgM, PE-conjugated CD23, and biotinylated CD21 followed by IL-2 as described previously (25). NK cells from D0.11 mice did not ex- allophycocyanin-conjugated streptavidin. The cells were sorted on a FACS hibit properties different from BALB/c mice. When necessary, residual T DIVA (BD Biosciences). For FACS analysis, the FACScan flow cytometer cells if detected by FACS in the propagated NK cells were depleted with (BD Biosciences) was used. biotinylated anti-CD3⑀ and streptavidin-conjugated magnetic beads (Milte- nyi Biotec). Quasi-monoclonal (QM) mice originally generated by Cas- Results calco et al. (26) were provided by Dr. R. Noelle (Dartmouth Medical Cen- Parameters of B cell induction of IL-13 mRNA synthesis by NK ter, Hanover, NH).
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