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Evaluation of the Class I Peptide Repertoire Toward a Definition Of Toward a Definition of Self: Proteomic Evaluation of the Class I Peptide Repertoire Heather D. Hickman, Angela D. Luis, Rico Buchli, Steven R. Few, Muthuraman Sathiamurthy, Rodney S. VanGundy, This information is current as Christopher F. Giberson and William H. Hildebrand of September 23, 2021. J Immunol 2004; 172:2944-2952; ; doi: 10.4049/jimmunol.172.5.2944 http://www.jimmunol.org/content/172/5/2944 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2004/02/20/172.5.2944.DC1 Material References This article cites 41 articles, 13 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/172/5/2944.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 23, 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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Toward a Definition of Self: Proteomic Evaluation of the Class I Peptide Repertoire1 Heather D. Hickman,* Angela D. Luis,* Rico Buchli,† Steven R. Few,* Muthuraman Sathiamurthy,* Rodney S. VanGundy,† Christopher F. Giberson,† and William H. Hildebrand2*† MHC class I molecules present host- and pathogen-derived peptides for immune surveillance. Much attention is given to the search for viral and tumor nonself peptide epitopes, yet the question remains, “What is self?” Analyses of Edman motifs and of small sets of individual peptides suggest that the class I self repertoire consists of thousands of different peptides. However, there exists no systematic characterization of this self-peptide backdrop, causing the definition of class I-presented self to remain largely hypo- thetical. To better understand the breadth and nature of self proteins sampled by class I HLA, we sequenced >200 endogenously loaded HLA-B*1801 peptides from a human B cell line. Peptide-source proteins, ranging from actin-related protein 6 to zinc finger Downloaded from protein 147, possessed an assortment of biological and molecular functions. Major categories included binding proteins, catalytic proteins, and proteins involved in cell metabolism, growth, and maintenance. Genetically, peptides encoded by all chromosomes were presented. Statistical comparison of proteins presented by class I vs the human proteome provides empiric evidence that the range of proteins sampled by class I is relatively unbiased, with the exception of RNA-binding proteins that are over-represented in the class I peptide repertoire. These data show that, in this cell line, class I-presented self peptides represent a comprehensive http://www.jimmunol.org/ and balanced summary of the proteomic content of the cell. Importantly, virus- and tumor-induced changes in virtually any cellular compartment or to any chromosome can be expected to be presented by class I molecules for immune recognition. The Journal of Immunology, 2004, 172: 2944–2952. ajor histocompatibility complex class I molecules are sentation is also pertinent to clinical transplantation: can we expect heterotrimeric cell surface glycoproteins that convey minor histocompatibility Ags to be derived from allogeneic poly- M intracellular fitness to immune effector cells (1, 2). morphisms throughout the human genome, or are person-to-person Class I molecules are assembled in the endoplasmic reticulum, differences in select proteins more subject to presentation? Finally, where they become loaded with endogenously synthesized host as have studies of nucleotide and amino acid sequences increased by guest on September 23, 2021 peptides before egress to the cell surface (3–5). Cells displaying our knowledge of evolution, understanding the breadth of the pro- class I with healthy host-derived peptide ligands remain unharmed, teome sampled will further expose the evolutionary pressures that while cells exhibiting peptide ligands unique to diseased cells be- have shaped the immune function of MHC class I molecules. come targets for the immune response (6–8). Immune effector MHC class I biologists have theorized that no self protein pre- discrimination of diseased and healthy cells is therefore contingent cursors are excluded from the class I peptide-presentation path- upon class I presentation of short (8–13 aa) endogenous peptides. way, although this hypothesis has been pieced together from in- Understanding the breadth of the proteome sampled by class I dependent peptide-characterization experiments for multiple class HLA is vital to a number of immunologic fields. For instance, the I alleles (9). A more complete understanding of the boundaries of development of vaccines that target CTL to infected or neoplastic peptide sampling has been delayed by the relatively laborious tech- cells requires the identification of Ags or epitopes that distinguish niques associated with the sequencing of a large number of pep- the unhealthy cell. Are viral Ags that localize to the nucleus less tides from any single class I molecule (for examples, see Ref. likely to be presented to CTL than a viral protein that resides 10–13). For instance, the most well-characterized class I molecule, preferentially in the Golgi apparatus? Will an up-regulated tumor HLA-A*0201, has ϳ110 documented endogenous ligands, most of Ag on chromosome 20 be better presented than a putative tumor which were identified in different laboratories using different tech- Ag on chromosome 7? Understanding the range of peptide pre- niques (14, 15). It cannot be ruled out that the small numbers of peptide-source proteins (i.e., the proteins from which the peptides *Department of Microbiology and Immunology, University of Oklahoma Health Sci- are derived) identified in each study are not a result of method- ences Center, Oklahoma City, OK 73104; and †Pure Protein LLC, Oklahoma City, ological differences (cell line, lysis method, affinity purification OK 73104 Ab, peptide-separation method, and ligand-sequencing method). Received for publication October 10, 2003. Accepted for publication December Thus, no individual study has systematically analyzed a large num- 16, 2003. ber of endogenously loaded class I peptide ligands to ascertain the 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 actual extent of peptide sampling of the human proteome. with 18 U.S.C. Section 1734 solely to indicate this fact. To explore the repertoire of self proteins presented as peptides 1 This work was supported by National Institutes of Health Contract NO1-AI-95360 by MHC class I molecules, we sequenced Ͼ200 peptides from (to W.H.H.). H.D.H. was supported by National Institutes of Health Training Grant HLA-B*1801 (the largest number of peptides reported from a sin- T32AI07633. gle experiment). A total of 10 mg of the B*1801 protein was iso- 2 Address correspondence and reprint requests to Dr. William H. Hildebrand, Depart- ment of Microbiology and Immunology, 975 NE 10th Street, Oklahoma City, OK lated from the class I-deficient 721.221 B cell line that has been 73104. E-mail address: [email protected] extensively used for class I protein expression. Peptides were Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 The Journal of Immunology 2945 eluted from B*1801, individual peptide ligands were selected for sequencing by mass spectrometry (MS), and proteomic techniques were applied for data analysis. In contrast to the close sequence relatedness of the bound peptides, the source proteins for these B*1801-bound peptides were found in almost every compartment of the cell and represented the spectrum of biological and cellular functions. Statistical analysis of peptide-source proteins in the con- text of the unbiased human proteome revealed a preference for RNA- and nucleic acid-binding proteins, ribosomal constituents, and cellular chaperones. These data provide the first direct evi- dence that a single class I molecule can access proteins from a large portion of, if not the entire, human proteome and present them as a sequence-related set of self peptides. Materials and Methods Cell line and transfectants Soluble HLA (sHLA)3-B*1801 was produced by transfection of the class I-negative EBV-transformed B-lymphoblastoid cell line 721.221 (16) with Downloaded from a PCR-truncated cDNA cloned into the vector PCDNA 3.1Ϫ (Invitrogen, Carlsbad, CA), as previously described (17). Class I production and purification sHLA-B*1801-producing transfectants were cultured in a CP-2500 Cell Pharm (Biovest International, Minneapolis, MN), and the sHLA-contain- ing supernatant was collected. Upon completing a bioreactor run, sHLA http://www.jimmunol.org/ complexes were affinity purified from the harvests obtained using W6/32 (18) coupled to a Sepharose 4B matrix (Amersham, Piscataway, NJ). Har- vests were applied to the
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