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dc.contributor.authorGil, Anna
dc.contributor.authorKamga, Larisa
dc.contributor.authorChirravuri-Venkata, Ramakanth
dc.contributor.authorAslan, Nuray
dc.contributor.authorClark, Fransenio G.
dc.contributor.authorGhersi, Dario
dc.contributor.authorLuzuriaga, Katherine
dc.contributor.authorSelin, Liisa K.
dc.date2022-08-11T08:09:55.000
dc.date.accessioned2022-08-23T16:49:11Z
dc.date.available2022-08-23T16:49:11Z
dc.date.issued2020-03-17
dc.date.submitted2020-04-08
dc.identifier.citation<p>Gil A, Kamga L, Chirravuri-Venkata R, Aslan N, Clark F, Ghersi D, Luzuriaga K, Selin LK. Epstein-Barr Virus Epitope-Major Histocompatibility Complex Interaction Combined with Convergent Recombination Drives Selection of Diverse T Cell Receptor α and β Repertoires. mBio. 2020 Mar 17;11(2):e00250-20. doi: 10.1128/mBio.00250-20. PMID: 32184241; PMCID: PMC7078470. <a href="https://doi.org/10.1128/mBio.00250-20">Link to article on publisher's site</a></p>
dc.identifier.issn2150-7511 (Electronic)
dc.identifier.doi10.1128/mBio.00250-20
dc.identifier.pmid32184241
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41411
dc.description.abstractRecognition modes of individual T cell receptors (TCRs) are well studied, but factors driving the selection of TCR repertoires from primary through persistent human virus infections are less well understood. Using deep sequencing, we demonstrate a high degree of diversity of Epstein-Barr virus (EBV)-specific clonotypes in acute infectious mononucleosis (AIM). Only 9% of unique clonotypes detected in AIM persisted into convalescence; the majority (91%) of unique clonotypes detected in AIM were not detected in convalescence and were seeming replaced by equally diverse "de novo" clonotypes. The persistent clonotypes had a greater probability of being generated than nonpersistent clonotypes due to convergence recombination of multiple nucleotide sequences to encode the same amino acid sequence, as well as the use of shorter complementarity-determining regions 3 (CDR3s) with fewer nucleotide additions (i.e., sequences closer to germ line). Moreover, the two most immunodominant HLA-A2-restricted EBV epitopes, BRLF1109 and BMLF1280, show highly distinct antigen-specific public (i.e., shared between individuals) features. In fact, TCRalpha CDR3 motifs played a dominant role, while TCRbeta played a minimal role, in the selection of TCR repertoire to an immunodominant EBV epitope, BRLF1. This contrasts with the majority of previously reported repertoires, which appear to be selected either on TCRbeta CDR3 interactions with peptide/major histocompatibility complex (MHC) or in combination with TCRalpha CDR3. Understanding of how TCR-peptide-MHC complex interactions drive repertoire selection can be used to develop optimal strategies for vaccine design or generation of appropriate adoptive immunotherapies for viral infections in transplant settings or for cancer. IMPORTANCE Several lines of evidence suggest that TCRalpha and TCRbeta repertoires play a role in disease outcomes and treatment strategies during viral infections in transplant patients and in cancer and autoimmune disease therapy. Our data suggest that it is essential that we understand the basic principles of how to drive optimum repertoires for both TCR chains, alpha and beta. We address this important issue by characterizing the CD8 TCR repertoire to a common persistent human viral infection (EBV), which is controlled by appropriate CD8 T cell responses. The ultimate goal would be to determine if the individuals who are infected asymptomatically develop a different TCR repertoire than those that develop the immunopathology of AIM. Here, we begin by doing an in-depth characterization of both CD8 T cell TCRalpha and TCRbeta repertoires to two immunodominant EBV epitopes over the course of AIM, identifying potential factors that may be driving their selection.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=32184241&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright © 2020 Gil et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectEBV
dc.subjectEpstein-Barr virus
dc.subjectT cell receptor
dc.subjectTCR
dc.subjectacute infectious mononucleosis
dc.subjectrepertoire
dc.subjectUMCCTS funding
dc.subjectHemic and Lymphatic Diseases
dc.subjectImmune System Diseases
dc.subjectImmunology and Infectious Disease
dc.subjectInfectious Disease
dc.subjectMicrobiology
dc.subjectVirus Diseases
dc.subjectViruses
dc.titleEpstein-Barr Virus Epitope-Major Histocompatibility Complex Interaction Combined with Convergent Recombination Drives Selection of Diverse T Cell Receptor alpha and beta Repertoires
dc.typeJournal Article
dc.source.journaltitlemBio
dc.source.volume11
dc.source.issue2
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5210&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4191
dc.identifier.contextkey17314520
refterms.dateFOA2022-08-23T16:49:11Z
html.description.abstract<p>Recognition modes of individual T cell receptors (TCRs) are well studied, but factors driving the selection of TCR repertoires from primary through persistent human virus infections are less well understood. Using deep sequencing, we demonstrate a high degree of diversity of Epstein-Barr virus (EBV)-specific clonotypes in acute infectious mononucleosis (AIM). Only 9% of unique clonotypes detected in AIM persisted into convalescence; the majority (91%) of unique clonotypes detected in AIM were not detected in convalescence and were seeming replaced by equally diverse "de novo" clonotypes. The persistent clonotypes had a greater probability of being generated than nonpersistent clonotypes due to convergence recombination of multiple nucleotide sequences to encode the same amino acid sequence, as well as the use of shorter complementarity-determining regions 3 (CDR3s) with fewer nucleotide additions (i.e., sequences closer to germ line). Moreover, the two most immunodominant HLA-A2-restricted EBV epitopes, BRLF1109 and BMLF1280, show highly distinct antigen-specific public (i.e., shared between individuals) features. In fact, TCRalpha CDR3 motifs played a dominant role, while TCRbeta played a minimal role, in the selection of TCR repertoire to an immunodominant EBV epitope, BRLF1. This contrasts with the majority of previously reported repertoires, which appear to be selected either on TCRbeta CDR3 interactions with peptide/major histocompatibility complex (MHC) or in combination with TCRalpha CDR3. Understanding of how TCR-peptide-MHC complex interactions drive repertoire selection can be used to develop optimal strategies for vaccine design or generation of appropriate adoptive immunotherapies for viral infections in transplant settings or for cancer.</p> <p>IMPORTANCE Several lines of evidence suggest that TCRalpha and TCRbeta repertoires play a role in disease outcomes and treatment strategies during viral infections in transplant patients and in cancer and autoimmune disease therapy. Our data suggest that it is essential that we understand the basic principles of how to drive optimum repertoires for both TCR chains, alpha and beta. We address this important issue by characterizing the CD8 TCR repertoire to a common persistent human viral infection (EBV), which is controlled by appropriate CD8 T cell responses. The ultimate goal would be to determine if the individuals who are infected asymptomatically develop a different TCR repertoire than those that develop the immunopathology of AIM. Here, we begin by doing an in-depth characterization of both CD8 T cell TCRalpha and TCRbeta repertoires to two immunodominant EBV epitopes over the course of AIM, identifying potential factors that may be driving their selection.</p>
dc.identifier.submissionpathoapubs/4191
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentDepartment of Pathology
dc.source.pagese00250-20


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Copyright © 2020 Gil et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Except where otherwise noted, this item's license is described as Copyright © 2020 Gil et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.