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Constitutive MHC Class II Expression Human Cytomegalovirus Disrupts

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Constitutive MHC Class II Expression Human Cytomegalovirus Disrupts Human Cytomegalovirus Disrupts Constitutive MHC Class II Expression Colleen M. Cebulla, Daniel M. Miller, Yingxue Zhang, Brian M. Rahill, Peter Zimmerman, John M. Robinson and Daniel This information is current as D. Sedmak of September 24, 2021. J Immunol 2002; 169:167-176; ; doi: 10.4049/jimmunol.169.1.167 http://www.jimmunol.org/content/169/1/167 Downloaded from References This article cites 79 articles, 40 of which you can access for free at: http://www.jimmunol.org/content/169/1/167.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 *average by guest on September 24, 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 © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Human Cytomegalovirus Disrupts Constitutive MHC Class II Expression1 Colleen M. Cebulla,* Daniel M. Miller,‡ Yingxue Zhang,* Brian M. Rahill,* Peter Zimmerman,* John M. Robinson,† and Daniel D. Sedmak2* CD8؉ and CD4؉ T lymphocytes are important in controlling human CMV (HCMV) infection, but the virus has evolved protean mechanisms to inhibit MHC-based Ag presentation and escape T lymphocyte immunosurveillance. Herein, the interaction of HCMV with the MHC class II Ag presentation pathway was investigated in cells stably transfected with class II transactivator. Flow cytometry experiments demonstrate that HCMV infection decreases cell-surface MHC class II expression. HCMV down- regulates MHC class II surface expression without a significant effect on class II RNA or steady-state protein levels. SDS-stability and confocal microscopy experiments demonstrate normal levels of steady-state peptide-loaded class II molecules in infected cells and that class II molecules reach late endosomal and HLA-DM positive peptide-loading compartments. However, MHC class II Downloaded from positive vesicles are retained in an abnormal perinuclear distribution. Finally, experiments with a mutant HCMV strain dem- onstrate that this novel mechanism of decreased MHC class II expression is not mediated by one of the known HCMV immu- nomodulatory genes. These defects in MHC class II expression combined with previously identified CMV strategies for decreasing MHC class I expression enables infected cells to evade T lymphocyte immunosurveillance. The Journal of Immunology, 2002, 169: 167–176. http://www.jimmunol.org/ ytomegalovirus is an important cause of morbidity and It is well-established that CD4ϩ T cells are important in con- mortality in immunocompromised populations, e.g., trolling CMV infection. Mice depleted of CD8ϩ T cells halt dis- AIDS patients and transplant recipients (1). Human seminated CMV disease with similar kinetics as nondepleted con- C 3 ϩ CMV (HCMV), like other HSVs, is able to persist for the life of trols, suggesting a compensatory antiviral role of the CD4 the host, even in immunocompetent individuals. Reactivation of population (18). In addition, clearance of CMV from the salivary latent or persistent virus is responsible for the majority of HCMV- gland, an organ important for persistence, is dependent on CD4ϩ associated morbidity and mortality in immunosuppressed hosts. T cells (19, 20). Control of CMV replication in the salivary gland ϩ ␥ Thus, determining the factors that promote HCMV persistence is a is dependent on CD4 T cells with the TH-1 phenotype and IFN- by guest on September 24, 2021 critical step in understanding and preventing HCMV disease. is an essential factor (20). CMV-specific CD4ϩ T cells play a Cell-mediated immunity is essential in controlling HCMV and critical role in controlling CMV infection through the release of other viral infections (2–7). However, viruses have evolved re- IFN-␥, but also have been shown to mediate cytolysis of infected markable strategies for evading cell-mediated immune responses cells in an MHC class II-restricted manner (20–23). (8). Moreover, a single virus can use multiple means of blocking CD4ϩ T cells recognize viral protein-derived peptides in the Ag presentation. For example, the HCMV US2, US3, US6, and context of MHC class II molecules. MHC class II proteins are US11 gene products use distinct mechanisms to inhibit MHC class constitutively expressed in APCs such as monocyte/macrophages, I Ag presentation and escape CD8ϩ T cell responses (9–16). In dendritic cells, and B cells. MHC class II ␣- and ␤-chains form a addition, the HCMV matrix protein pp65 inhibits the presentation heterodimer in the endoplasmic reticulum and associate with the of HCMV IE1 protein-derived peptides to IE1-specific CD8ϩ T invariant chain (Ii) to form a “nonameric” complex (24–26). This cells (17). complex moves through endosomal compartments to peptide-load- ing compartments where the HLA-DM molecule facilitates the ex- change of the class II-associated Ii peptide portion of Ii for pep- tides generated in lysosomal compartments (24, 26). Class II Departments of *Pathology, and †Physiology and Cell Biology, Ohio State University molecules present these peptides to CD4ϩ T cells on the cell College of Medicine and Public Health, Columbus, OH 43210; ‡Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL 33136 surface. ␥ Received for publication April 2, 2001. Accepted for publication April 29, 2002. CMV blocks IFN- -stimulated MHC class II expression in en- dothelial cells, an important site of CMV infection in vivo (27, 28). 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 HCMV inhibits IFN-␥ inducible MHC class II expression by with 18 U.S.C. Section 1734 solely to indicate this fact. blocking the JAK/STAT signal transduction pathway in infected 1 This research was supported by National Institutes of Health Grant RO1 AI38452- cells and murine CMV blocks IFN-␥-stimulated MHC class II ex- 01A1. A portion of this work was presented at the 7th International Cytomegalovirus Workshop. C.M.C. was a Presidential Fellow at Ohio State University. D.M.M. was pression through a JAK/STAT-independent mechanism (29–31). a Howard Hughes Medical Institute Predoctoral Fellow. HCMV infection decreases constitutive MHC class II expres- 2 Address correspondence and reprint requests to Dr. Daniel D. Sedmak, Department sion in monocyte/macrophages, a critical site of HCMV latency of Pathology, Ohio State University College of Medicine and Public Health, 129 and reactivation (32). There is evidence that the HCMV US2 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210. E-mail address: [email protected] glycoprotein, a molecule previously shown to target MHC class ␣ 3 Abbreviations used in this paper: HCMV, human CMV; CIITA, class II transacti- I H chains for degradation, mediates a decrease in HLA-DR vator; PFA, phosphonoformic acid; Ii, invariant chain. and HLA-DM expression at early times after infection (33). Copyright © 2002 by The American Association of Immunologists, Inc. 0022-1767/02/$02.00 168 HCMV DISRUPTS CONSTITUTIVE MHC CLASS II Given the fact that HCMV uses four distinct gene products to GATCCAGTTTGCAC-3Ј) and antisense (5Ј-GCCCTAGGATATTTAT block MHC class I expression and that these gene products GAAAAAGCCAGTGTGCC-3Ј). target distinct levels of the class I Ag processing pathway, we Northern blot analysis suspected additional, US2-independent mechanisms for the de- crease in MHC class II expression in infected cells. Total RNA from U373/CII and U373/pc was extracted at 0, 1, and 3 days after infection using the guanidine thiocyanate extraction and cesium chlo- Herein, we investigate the HCMV-mediated disruption of con- ride centrifugation method (36). The RNA was separated on a 1.4% aga- stitutive MHC class II expression by generating a model system rose 0.22-M formaldehyde gel. Northern blots were probed for HLA-DR␣ that facilitates molecular analyses. Monocyte/macrophages, which as well as the loading control GAPDH. Probes were generated using ran- 32 are an important site of HCMV infection in vivo and constitutively dom priming and [␣- P]dCTP (Deca Prime kit; Ambion, Austin, TX). ␣ express MHC class II, are not efficiently infected in vitro, thereby cDNA templates were generated for the HLA-DR probes using primer sets sense (5Ј-AAAGCGCTCCAACTATACTCCGA-3Ј) and antisense: limiting investigations of the molecular mechanism for decreased (5Ј-ACCCTGCAGTCGTAAACGTCC-3Ј) and clone p0A1 (ATCC) was class II in these primary cells. To generate a model to study the used for the GAPDH probes. Dilutional standards of 10, 5, and 2.5 ␮g interaction of HCMV with MHC class II, we transfected a class II RNA isolated from noninfected and HCMV-infected U373/CII were run as negative, HCMV permissive cell line, U373 astrocytoma cells, controls. Densitometry analyses were performed by scanning autoradio- graphic films with a Hewlett Packard flatbed scanner (Hewlett Packard, with class II transactivator (CIITA) cDNA, thereby creating cells Palo Alto, CA), and the digital images were analyzed using Scion Image that constitutively express class II molecules. CIITA is the “master software (Scion Corporation, Frederick, MD). switch” in class II expression, and transfection of CIITA into class II negative cells results in constitutive MHC class II, Ii, and Flow cytometry HLA-DM expression (34). U373 cells are permissive for HCMV Cells were harvested with trypsin/EDTA, labeled with directly conjugated Downloaded from infection and have been used for investigating HCMV/MHC class fluorescein-labeled Abs, and washed three times with SBSS.
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