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Heteroclitic CD8 T Cell Epitopes Enhanced Antiviral Immunity Structural and Functional Correlates of Enhanced Antiviral Immunity Generated by Heteroclitic CD8 T Cell Epitopes This information is current as Jonathan A. Trujillo, Stephanie Gras, Kelly-Anne Twist, of September 30, 2021. Nathan P. Croft, Rudragouda Channappanavar, Jamie Rossjohn, Anthony W. Purcell and Stanley Perlman J Immunol 2014; 192:5245-5256; Prepublished online 2 May 2014; doi: 10.4049/jimmunol.1400111 Downloaded from http://www.jimmunol.org/content/192/11/5245 References This article cites 56 articles, 31 of which you can access for free at: http://www.jimmunol.org/content/192/11/5245.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 by guest on September 30, 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 © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Structural and Functional Correlates of Enhanced Antiviral Immunity Generated by Heteroclitic CD8 T Cell Epitopes Jonathan A. Trujillo,*,1 Stephanie Gras,†,1 Kelly-Anne Twist,† Nathan P. Croft,† Rudragouda Channappanavar,‡ Jamie Rossjohn,†,x,{,2 Anthony W. Purcell,†,2 and Stanley Perlman*,‡,2 Peptides that bind poorly to MHC class I molecules often elicit low–functional avidity T cell responses. Peptide modification by altering the anchor residue facilitates increased binding affinity and may elicit T cells with increased functional avidity toward the native epitope (“heteroclitic”). This augmented MHC binding is likely to increase the half-life and surface density of the hetero- clitic complex, but precisely how this enhanced T cell response occurs in vivo is not known. Furthermore, the ideal heteroclitic epitope will elicit T cell responses that completely cross-react with the native epitope, maximizing protection and minimizing undesirable off-target effects. Such epitopes have been difficult to identify. In this study, using mice infected with a murine Downloaded from coronavirus that encodes epitopes that elicit high (S510, CSLWNGPHL)– and low (S598, RCQIFANI)–functional avidity responses, we show that increased expression of peptide S598 but not S510 generated T cells with enhanced functional avidity. Thus, immune responses can be augmented toward T cell epitopes with low functional avidity by increasing Ag density. We also identified a heteroclitic epitope (RCVIFANI) that elicited a T cell response with nearly complete cross-reactivity with native epitope and demonstrated increased MHC/peptide abundance compared with native S598. Structural and thermal melt analyses indicated that the Q600V substitution enhanced stability of the peptide/MHC complex without greatly altering the antigenic http://www.jimmunol.org/ surface, resulting in highly cross-reactive T cell responses. Our data highlight that increased peptide/MHC complex display contributes to heteroclitic epitope efficacy and describe parameters for maximizing immune responses that cross-react with the native epitope. The Journal of Immunology, 2014, 192: 5245–5256. athogen and tumor clearance both require effective T cell avidity T cell responses that are neither protective against patho- responses; therefore, any vaccines designed to enhance gen exposure nor efficacious in diminishing tumor burden (3–9). immune protection against infectious diseases or cancer Several approaches have been used to enhance the functional P by guest on September 30, 2021 should include relevant CD8 or CD4 T cell epitopes (1, 2). avidity of T cell responses to tumor and viral Ags, including use of However, some subdominant epitopes recognized in infectious potent adjuvants during immunization (10), adoptive immuno- settings and from many tumors induce weak, low–functional therapy of high-avidity T cell clones (11, 12), and immunization with optimized peptides, including heteroclitic peptides; the latter, although altered in sequence, result in augmented T cell responses *Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242; to the native epitope (2, 13, 14). † Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Heteroclitic CD8 T cell epitopes were initially identified in the Monash University, Clayton, Victoria 3800, Australia; ‡Department of Microbiology, University of Iowa, Iowa City, IA 52242; xAustralian Research Council Centre of context of tumors (13). In most instances, heteroclitic peptides Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria { display enhanced binding to the MHC molecule (15, 16), although 3800, Australia; and Institute of Infection and Immunity, Cardiff University School heteroclitic peptides that augment binding to the TCR have also of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom been identified (e.g., see Ref. 17). Heteroclitic epitopes exhibiting 1J.A.T. and S.G. contributed equally to this work. 2 augmented MHC class I (MHCI) binding and potentially greater J.R., A.W.P., and S.P. are joint senior authors. effective peptide/MHC complex (pMHC) surface density may Received for publication January 14, 2014. Accepted for publication April 1, 2014. induce a higher functional avidity T cell response. However, This work was supported by National Institutes of Health Grant R01 NS036592 and whether increased pMHCI levels actually result in enhanced National Health and Medical Research Council of Australia (NHMRC) Project Grant 1023141. A.W.P. is an NHMRC Senior Research Fellow. J.R. is an NHMRC Australia functional avidity has not been established because several in vitro Fellow. J.A.T. was supported by predoctoral individual National Research Service studies showed that low levels of peptide expressed on the surface Award National Institutes of Health Grant AI093129. S.G. is an Australian Research of APCs induced CD8 T cells with high functional avidity. Con- Council Future Fellow. versely, higher levels of pMHCI expression resulted in the out- The atomic coordinates and structure factors presented in this article have been submitted to the Protein Data Bank (http://www.pdb.org/pdb/home/home.do) under growth of cells with lower avidity for the pMHCI (3). Based on accession numbers 4PV8 and 4PV9. these in vitro observations, weakly immunogenic epitopes, which Address correspondence and reprint requests to Dr. Stanley Perlman, University of often result from low-affinity pMHCI interactions and subse- Iowa, Department of Microbiology, 3-712 BSB, Iowa City, IA 52242. E-mail address: quently exhibit low pMHCI density, would be predicted to induce [email protected] high–functional avidity responses. The relationship between the Abbreviations used in this article: Aba, aminobutyric acid; B6, C57BL/6; DC, den- dritic cell; JHMV, JHM strain of mouse hepatitis virus; MHCI, MHC class I; MRM, level of pMHCI on the surface of APCs and the subsequent CD8 multiple reaction monitoring; p.i., postinfection; pMHC, peptide/MHC complex; T cell response has also been investigated in vivo (18–20). In- pMHCI, peptide/MHC class I complex; rJ, recombinant version of JHMV; r.m.s.d., creased epitope density raised the magnitude of the response but root mean square deviation; t , melting temperature; VacV, vaccinia virus. m did not affect the functional avidity of the primary immune re- Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 sponse. Importantly, none of these in vitro or in vivo studies have www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400111 5246 HETEROCLITIC EPITOPES IN CORONAVIRUS ENCEPHALOMYELITIS examined the relationship between pMHCI density and functional heteroclitic epitopes function, levels of both Kb/Q600V and Kb/ avidity of the T cell response elicited toward a weakly immuno- Q600Y were increased compared with Kb/S598. genic epitope and its corresponding heteroclitic analog. One concern with the use of heteroclitic epitopes is that a var- Materials and Methods iable fraction of the response may recognize only the modified Mice and not the native epitope (21). The outgrowth of cells that recognize only the modified epitope is not only futile as a Six- to 8-wk-old pathogen-free B6 mice were purchased from the National Cancer Institute (Frederick, MD) and housed in the Animal Care Facility at vaccine strategy but raises the possibility that the modified the University of Iowa. This study was carried out in strict accordance with the epitope-specific response could also respond to a self-epitope. recommendations in the GuidefortheCareandUseofLaboratoryAnimals This could initiate or contribute to the development of auto- of the National Institutes of Health. Animal experiments were approved by immune disease, thus making the use of heteroclitic peptides in the Institutional Animal Care and Use Committee at the University of Iowa. clinical settings problematic. Viruses Mice infected with a murine coronavirus, the
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