Glomerulonephritis Humoral Responses and Immune Complex
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CD100 Enhances Dendritic Cell and CD4+ Cell Activation Leading to Pathogenetic Humoral Responses and Immune Complex Glomerulonephritis This information is current as of September 27, 2021. Ming Li, Kim M. O'Sullivan, Lynelle K. Jones, Timothy Semple, Atsushi Kumanogoh, Hitoshi Kikutani, Stephen R. Holdsworth and A. Richard Kitching J Immunol 2006; 177:3406-3412; ; doi: 10.4049/jimmunol.177.5.3406 Downloaded from http://www.jimmunol.org/content/177/5/3406 References This article cites 31 articles, 18 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/177/5/3406.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 September 27, 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CD100 Enhances Dendritic Cell and CD4؉ Cell Activation Leading to Pathogenetic Humoral Responses and Immune Complex Glomerulonephritis1 Ming Li,* Kim M. O’Sullivan,* Lynelle K. Jones,* Timothy Semple,* Atsushi Kumanogoh,† Hitoshi Kikutani,† Stephen R. Holdsworth,* and A. Richard Kitching2* CD100, a member of the semaphorin family, is a costimulatory molecule in adaptive immune responses by switching off CD72’s negative signals. However, CD100’s potential pathogenetic effects in damaging immune responses remain largely unexplored. We tested the hypothesis that CD100 plays a pathogenetic role in experimental immune complex glomerulonephritis. Daily injection of horse apoferritin for 14 days induced immune complex formation, mesangial proliferative glomerulonephritis and proteinuria ؉/؉ ؊/؊ in CD100-intact (CD100 ) BALB/c mice. CD100-deficient (CD100 ) mice were protected from histological and functional Downloaded from glomerular injury. They exhibited reduced deposition of Igs and C3 in glomeruli, reduced MCP-1 and MIP-2 intrarenal mRNA expression, and diminished glomerular macrophage accumulation. Attenuated glomerular injury was associated with decreased Ag-specific Ig production, reduced CD4؉ cell activation and cytokine production. Following Ag injection, CD4؉ cell CD100 expression was enhanced and dendritic cell CD86 expression was up-regulated. However, in CD100؊/؊ mice, dendritic cell CD86 (but not CD80) up-regulation was significantly attenuated. Following i.p. immunization, CD86, but not CD80, promotes early ؉ Ag-specific TCR-transgenic DO11.10 CD4 cell proliferation and IFN-␥ production, suggesting that CD100 expression enables full http://www.jimmunol.org/ expression of CD86 and consequent CD4؉ cell activation. Transfer of CD100؉/؉ DO11.10 cells into CD100؊/؊ mice resulted in decreased proliferation demonstrating that CD100 from other sources in addition to CD100 from Ag-specific CD4؉ cells plays a role in initial T cell proliferation. Although T cell-B cell interactions also may be relevant, these studies demonstrate that CD100 enhances pathogenetic humoral immune responses and promotes the activation of APCs by up-regulating CD86 expression. The Journal of Immunology, 2006, 177: 3406–3412. he CD100 (Sema4D) is a 150-kDa transmembrane protein responses are defective in CD100-deficient (CD100Ϫ/Ϫ) mice (7), of the class IV semaphorin subfamily (1–3), identified as whereas adaptive immune responses are significantly enhanced in by guest on September 27, 2021 T an inhibitor of axonal growth in neuronal development (4, CD100 transgenic mice that expressed a truncated form of CD100 5), but also expressed by cells of the immune system and involved (8). In addition, costimulatory signals mediated via CD100 result in immune responses (6–8). CD100 is expressed constitutively on in the activation of Ag-specific T cells by enhancing DC matura- resting T cells, but weakly on resting B cells and APCs (9, 10). tion (9). However, there is limited information on the functional CD100 expression is significantly up-regulated after stimulation role of CD100 in pathological inflammatory responses. One study (1, 9, 10) and mediates intracellular responses via ligation of its in experimental autoimmune encephalomyelitis showed that cell surface receptor CD72, which is expressed on B cells and CD100Ϫ/Ϫ mice were protected from disease (9). It is unclear 3 splenic dendritic cells (DCs) (3, 6, 7, 9, 10). Binding of CD100 to whether this pathogenetic role of CD100 extends to other forms of CD72 induces tyrosine dephosphorylation of CD72, resulting in tissue-specific diseases mediated by immune responses, particu- dissociation of CD72 from Src homology region 2 domain-con- larly humoral responses. taining tyrosine phosphatase-1 (6, 10, 11), the attenuation of neg- Glomerulonephritis (GN) is an important cause of renal disease, ative signaling, and the enhancement of immune responses. Stud- usually caused by injurious adaptive immune responses. The dif- ies in genetically modified mice have shown an important role for ferent types and patterns of injury in GN are due in part to the CD100 in both T and B cell responses. T cell priming and B cell participation of both humoral and cellular effector mechanisms (12). Circulating immune complexes, formed by the interaction of *Centre for Inflammatory Diseases, Monash University Department of Medicine, soluble Ag with Ab are important in the pathogenesis of number of Clayton, Victoria, Australia; and †Department of Molecular Immunology, Research renal diseases, including lupus nephritis, postinfectious GN, and Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan serum sickness (13), and cause glomerular injury via disruption of Received for publication May 24, 2005. Accepted for publication May 25, 2006. the glomerular architecture, activation of the complement path- The costs of publication of this article were defrayed in part by the payment of page way, and the recruitment of effector leukocytes. Although some charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. studies have shown a role for CD40 and members of the B7 family 1 This work was supported by grants from the National Health and Medical Research in both autoimmune and nonautoimmune GN (14–17), the role of Council of Australia. CD100 in the development of GN is not known. To test the hy- 2 Address correspondence and reprint requests to Dr. A. Richard Kitching, Centre for pothesis that CD100 plays a pathogenetic role in humorally me- Inflammatory Diseases, Monash University Department of Medicine, Monash Med- diated GN, GN was induced by injecting a foreign Ag (apoferritin) ical Centre, Clayton 3168, Victoria, Australia. E-mail address: Richard. ϩ/ϩ [email protected] into CD100 wild-type (CD100 ) mice and mice genetically 3 Abbreviations used in this paper: DC, dendritic cell; GN, glomerulonephritis; PAS, deficient in CD100. This model is characterized by immune periodic acid-Schiff; PI, propidium iodide; MHC II, MHC class II. responses against apoferritin, immune complex deposition in Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 The Journal of Immunology 3407 glomeruli, mesangial cell proliferation, the accumulation of mac- in 96-well plates in triplicate in complete culture medium (10% FCS/RPMI rophages in glomeruli, and proteinuria (18). These studies demon- 1640, supplied with L-glutamine, 2-ME) in the presence or absence of strate that CD100 plays a pathogenetic role in humorally mediated horse apoferritin (72 h). Cells were pulsed with 0.5 Ci/well thymidine ([3H]TdR) for the last 18 h, and the incorporation of the [3H]TdR was injury affecting the kidney by enhancing DC function and up-reg- ϩ detected with a liquid scintillation beta counter (Wallac 1409; Cambridge ulating CD4 T cell priming and subsequent B cell activation. Scientific). Results are expressed as follows: stimulation index ϭ stimu- lated group cpm/unstimulated group cpm. Materials and Methods Measurement of cytokine production by Ag-stimulated Mice and induction of immune complex GN lymphocytes CD100Ϫ/Ϫ BALB/c mice (7) and DO11.10 mice (19) (The Jackson Lab- Splenocytes were prepared as above. After three washes with HF2.5, cells oratory) were bred at Monash Medical Centre (Clayton, Victoria, Austra- were incubated in 24-well plates (4 ϫ 106 cells/ml in 10% FCS/RPMI 1640 lia). Male BALB/c mice (8–12 wk of age) were obtained from Monash with L-glutamine, 2-ME, 72 h with 40 g/ml horse apoferritin). IFN-␥ and University Centre Animal Services. All mice were maintained in specific IL-4 in culture supernatant were measured by ELISA as previously de- pathogen-free conditions. Studies were approved by the Monash University scribed (23). The Abs used were rat anti-mouse IFN-␥ (R4-6A2; BD (Monash Medical Centre Committee B) Animal Ethics Committee. Four Pharmingen), biotinylated rat anti-mouse IFN-␥ (XMG1.2; BD Pharmin- milligrams