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Cells Promote Survival and Differentiation of B Up-Regulated In Expression of the Adaptor Protein Hematopoietic Src Homology 2 is Up-Regulated in Response to Stimuli That Promote Survival and Differentiation of B This information is current as Cells of September 28, 2021. Brantley R. Herrin and Louis B. Justement J Immunol 2006; 176:4163-4172; ; doi: 10.4049/jimmunol.176.7.4163 http://www.jimmunol.org/content/176/7/4163 Downloaded from References This article cites 48 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/176/7/4163.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 28, 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 Expression of the Adaptor Protein Hematopoietic Src Homology 2 is Up-Regulated in Response to Stimuli That Promote Survival and Differentiation of B Cells Brantley R. Herrin and Louis B. Justement1 Analysis of hematopoietic Src homology 2 (HSH2) protein expression in mouse immune cells demonstrated that it is expressed at low levels in resting B cells but not T cells or macrophages. However, HSH2 expression is up-regulated within 6–12 h in response to multiple stimuli that promote activation, differentiation, and survival of splenic B cells. HSH2 expression is increased in response to anti-CD40 mAb, the TLR ligands LPS and CpG DNA, and B lymphocyte stimulator (BLyS), a key regulator of peripheral B cell survival and homeostasis. Stimulation of B cells with anti-CD40 mAb, LPS, CpG DNA, or BLyS has previously been shown to induce activation of NF-␬B. In agreement with this finding, up-regulation of HSH2 expression in response to these Downloaded from stimuli is blocked by inhibitors of NF-␬B activation and is potentiated by stimulation with PMA, suggesting that HSH2 expression is dependent on NF-␬B activation. In contrast to CD40, BAFF receptor, TLR4, and TLR9 mediated signaling, stimulation of splenic B cells via the BCR was not observed to induce expression of HSH2 unless the cells had been stimulated previously through CD40. Finally, HSH2 expression is down-regulated in splenic B cells in response to stimulation with IL-21, which has been shown to induce apoptosis, even in the presence of anti-CD40 mAb, LPS, or CpG DNA. IL-21 stimulation also results in down-regulation of antiapoptotic proteins such as Bcl-xL and up-regulation of proapoptotic proteins like Bim. Therefore, HSH2 expression is http://www.jimmunol.org/ coordinately up-regulated with known antiapoptotic molecules and directly correlates with B cell survival. The Journal of Immunology, 2006, 176: 4163–4172. he importance of adaptor proteins in regulating lympho- lineage cells based primarily on analysis of mRNA and in one cyte development, activation, and differentiation is well instance detection of protein by Western blotting (5, 6). T documented (1–4). Recent studies have begun to charac- Subsequent experiments demonstrated that human HSH2 pro- terize the role of the adaptor protein hematopoietic Src homology tein physically interacts with the protein tyrosine kinase c-Fes and 2 (HSH2),2 also known as adaptor in lymphocytes of unknown the Cdc42-associated protein tyrosine kinase ACK1 based on ex- function X (ALX), in regulation of lymphocyte biology (5–8). In pression of recombinant proteins in 293 cells (5). Thus, it was by guest on September 28, 2021 the original report documenting cloning of human HSH2, Northern hypothesized that HSH2 may be involved in cytokine-induced sig- blot analysis detected mRNA for HSH2 in spleen and PBL (5). naling in myelomonocytic cells by virtue of its putative interaction RT-PCR was also used to detect message for HSH2 in thymus, with c-Fes or it could possibly be involved in regulating cytoskel- spleen, and PBL. A more detailed analysis of HSH2 expression etal reorganization through an ACK1-Cdc42-dependent pathway; using RT-PCR detected message in T and B cells as well as mono- these predictions were not tested, however. Expression of human cytes isolated from peripheral blood (5). More recently, the mouse HSH2 (ALX) in the Jurkat T cell line was shown to inhibit IL-2 homolog of HSH2 (ALX) was cloned and Northern blot analysis promoter activation (6). In particular, it was shown that in response was used to detect mRNA for murine HSH2 in spleen and thymus to stimulation of cells with anti-CD28 and PMA, HSH2 had the (6). Western blotting with a polyclonal antiserum against human greatest inhibitory effect on activation of the composite RE/AP HSH2 detected expression of the adaptor in T and B cell lines as ϩ element (CD28 responsive element in conjunction with a noncon- well as PBMC and CD4 T cells (6). Thus, initial studies sug- gested that HSH2 is expressed in lymphoid as well as myeloid sensus AP-1 site) and that its inhibitory activity was dependent on the Src homology 2 domain (6, 7). Thus, it was hypothesized that HSH2 is a structural/functional homolog of the T cell-specific adapter protein TSAd and that it regulates IL-2 production down- Division of Developmental and Clinical Immunology, Department of Microbiology, stream of CD28 during costimulation of T cell activation (7). University of Alabama, Birmingham, AL 35294 We performed experiments to assess the function of mouse Received for publication August 31, 2005. Accepted for publication January 26, 2006. HSH2 protein using the WEHI-231 cell line and demonstrated that The costs of publication of this article were defrayed in part by the payment of page retroviral induced expression of HSH2 protects cells from under- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. going BCR-induced apoptosis (8). Although exogenous expression 1 Address correspondence and reprint requests to Dr. Louis B. Justement, Division of of HSH2 was not observed to cause widespread quantitative or Developmental and Clinical Immunology, Department of Microbiology, University of qualitative changes in BCR signaling, it did selectively potentiate Alabama at Birmingham, 378 Wallace Tumor Institute, 1824 6th Avenue South, JNK activation in response to BCR ligation. Retroviral-mediated Birmingham, AL 35294-3300. E-mail address: [email protected] expression of HSH2 was observed to maintain mitochondrial sta- 2 Abbreviations used in this paper: HSH2, hematopoietic Src homology 2; ALX, adaptor in lymphocytes of unknown function X; BLyS, B lymphocyte stimulator; bility in WEHI-231 cells treated with anti-Ig Ab, suggesting that BAFF, B cell-activating factor belonging to the TNF family; BAFF-R, BAFF recep- this adaptor may regulate distal processes that affect mitochondrial tor; Tg, transgenic; mIgM, membrane IgM; mIgD, membrane IgD; HEL, hen egg Ј stability (8). Analysis of endogenous HSH2 expression revealed lysozyme; PDTC, pyrolidine dithiocarbamate; DiOC6, 3,3 -dihexyloxacarbocyanine iodide; 7AAD, 7-aminoactinomycin D. that this adaptor is constitutively expressed in the WEHI-231 cell Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 4164 REGULATION OF HSH2 EXPRESSION IN B LYMPHOCYTES line, but that the level of HSH2 detected by Western blotting de- indicated. For NF-␬B inhibition experiments, purified B lymphocytes were creases within 8–12 h in response to BCR ligation. Importantly, preincubated for 30 min with 1–5 mM PDTC or 0.5–2.0 ␮M Bay 11-7082 ␬ studies further demonstrated that CD40-dependent protection of before addition of other stimuli. Viability of cells treated with NF- B in- hibitors was monitored based on staining with 7-aminoactinomycin D WEHI-231 cells from BCR-mediated apoptosis is associated with (7AAD). Unless otherwise noted, HSH2 expression was assayed at 12 h up-regulation and maintenance of endogenous HSH2 expression Ј poststimulation, whereas 3,3 -dihexyloxacarbocyanine iodide (DiOC6) (8). Thus, HSH2 expression mediated by retroviral transduction or staining was assayed at 24 h. B cells were cultured in medium alone (no CD40-dependent signaling was observed to directly correlate with treatment) for 12, 24, or 48 h, depending on the assay being performed and survival of WEHI-231 cells stimulated via the BCR. the longest time point analyzed. Splenic CD4ϩ T cells were purified from C57BL/6 mice using the To gain insight into the functional role of HSH2 in the immune ϩ MACS CD4 T cell isolation kit according to the manufacturer’s instruc- system, experiments were performed to examine mouse HSH2 ex- tions (Miltenyi Biotec). Briefly, single cell suspensions of mouse spleno- pression at the protein level in normal hemopoietic cell popula- cytes were first incubated with a mixture of biotinylated Abs (anti-CD8␣, tions. Studies revealed that HSH2 is expressed at low levels in anti-B220, anti-DX5, anti-CD11b, and anti-Ter-119), then anti- ϩ unstimulated splenic B cells, and its expression is significantly biotin-conjugated magnetic MACS beads were added to deplete non-CD4 Ͼ ϩ up-regulated in response to a wide range of stimuli that are known T cells. Isolated cells were 95% CD4 as verified using flow cytometric analysis. Purified T cells (2 ϫ 106 cells/ml) were cultured at 37°C under to promote B cell survival and differentiation, including LPS, CpG 5% CO2 in RPMI 1640 supplemented as earlier described.
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