Human TCR as antigen

Homologies and potentially cross- reactive HLA-DR2-restricted epitopes within the AV and BV CDR2 loops

Arthur Vandenbark, Nicole Culbertson, Tom Finn, David Barnes, Abigail Buenafe, Gregory G. Burrows, Sandra Law, Yuan K. Chou, Halina Offner

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The major function of the T-cell receptor is to confer antigen specificity to T cells. However, nascent TCR proteins that are not assembled into functional heterodimers may be processed and displayed with self MHC molecules on the T-cell surface, and are thought to be the genesis of autoregulatory T cells that can limit inflammatory responses through T-T network interactions. In previous work, we and others have exploited this natural regulatory system using TCR peptides to amplify regulatory T cells that potentially can treat human autoimmune diseases such as multiple sclerosis (MS) and arthritis. The development of this approach is limited by the diversity of human TCR V gene sequences, and by lack of knowledge of exactly which regions of the V gene proteins are immunogenic in association with various MHC alleles. To identify similar amino acid sequences within and among human V gene families that might have immunologic cross reactivity, we aligned 74 known AV and 109 known BV protein sequences into homologous groups using the ClustalX program. Moreover, with a focus on CDR2 peptides that have previously been used to induce regulatory T cells in clinical trials, we established homologous peptide groups, and then identified the optimal amino acid motifs for binding to two alleles, HLA-DRB1*1501 and DRB5*0101, that have been associated with susceptibility to MS. From this analysis, > 75% of AV and BV CDR2 sequences were predicted to bind with at least moderate avidity to each of the DR2 alleles, thus enhancing the likelihood that they could be antigenic. Further ordering of putative TCR contact residues revealed a different set of homology groupings, including many intrafamily sequence matches and some interfamily matches that might allow immunological cross reactivity. Particularly striking were DRB1*1501-restricted IH-S and IY-S motifs shared by BV11, BV12, and BV13 and BV3, BV12, BV13, and BV17 family members, respectively, and DRB5*0101-restricted RL-H and RL-Y motifs shared by BV11, BV12, and BV13 and BV13 and BV17 family members, respectively. This analysis may be useful in designing an array of clinically useful homologous peptides with optimal MHC binding properties and highly cross-reactive TCR binding motifs.

Original languageEnglish (US)
Pages (from-to)57-83
Number of pages27
JournalCritical Reviews in Immunology
Volume20
Issue number1
StatePublished - 2000

Fingerprint

HLA-DR2 Antigen
Epitopes
Antigens
Peptides
Alleles
Regulatory T-Lymphocytes
HLA-DRB5 Chains
Multiple Sclerosis
T-Cell Antigen Receptor Specificity
T-Lymphocytes
HLA-DRB1 Chains
Amino Acid Motifs
Proteins
Sequence Homology
T-Cell Antigen Receptor
Genes
Autoimmune Diseases
Arthritis
Amino Acid Sequence
Clinical Trials

Keywords

  • Network regulation
  • TCR peptide vaccination
  • V gene epitopes

ASJC Scopus subject areas

  • Immunology

Cite this

Human TCR as antigen : Homologies and potentially cross- reactive HLA-DR2-restricted epitopes within the AV and BV CDR2 loops. / Vandenbark, Arthur; Culbertson, Nicole; Finn, Tom; Barnes, David; Buenafe, Abigail; Burrows, Gregory G.; Law, Sandra; Chou, Yuan K.; Offner, Halina.

In: Critical Reviews in Immunology, Vol. 20, No. 1, 2000, p. 57-83.

Research output: Contribution to journalArticle

Vandenbark, Arthur ; Culbertson, Nicole ; Finn, Tom ; Barnes, David ; Buenafe, Abigail ; Burrows, Gregory G. ; Law, Sandra ; Chou, Yuan K. ; Offner, Halina. / Human TCR as antigen : Homologies and potentially cross- reactive HLA-DR2-restricted epitopes within the AV and BV CDR2 loops. In: Critical Reviews in Immunology. 2000 ; Vol. 20, No. 1. pp. 57-83.
@article{5b0f05741ce54ae2a4b5f6cb136125a1,
title = "Human TCR as antigen: Homologies and potentially cross- reactive HLA-DR2-restricted epitopes within the AV and BV CDR2 loops",
abstract = "The major function of the T-cell receptor is to confer antigen specificity to T cells. However, nascent TCR proteins that are not assembled into functional heterodimers may be processed and displayed with self MHC molecules on the T-cell surface, and are thought to be the genesis of autoregulatory T cells that can limit inflammatory responses through T-T network interactions. In previous work, we and others have exploited this natural regulatory system using TCR peptides to amplify regulatory T cells that potentially can treat human autoimmune diseases such as multiple sclerosis (MS) and arthritis. The development of this approach is limited by the diversity of human TCR V gene sequences, and by lack of knowledge of exactly which regions of the V gene proteins are immunogenic in association with various MHC alleles. To identify similar amino acid sequences within and among human V gene families that might have immunologic cross reactivity, we aligned 74 known AV and 109 known BV protein sequences into homologous groups using the ClustalX program. Moreover, with a focus on CDR2 peptides that have previously been used to induce regulatory T cells in clinical trials, we established homologous peptide groups, and then identified the optimal amino acid motifs for binding to two alleles, HLA-DRB1*1501 and DRB5*0101, that have been associated with susceptibility to MS. From this analysis, > 75{\%} of AV and BV CDR2 sequences were predicted to bind with at least moderate avidity to each of the DR2 alleles, thus enhancing the likelihood that they could be antigenic. Further ordering of putative TCR contact residues revealed a different set of homology groupings, including many intrafamily sequence matches and some interfamily matches that might allow immunological cross reactivity. Particularly striking were DRB1*1501-restricted IH-S and IY-S motifs shared by BV11, BV12, and BV13 and BV3, BV12, BV13, and BV17 family members, respectively, and DRB5*0101-restricted RL-H and RL-Y motifs shared by BV11, BV12, and BV13 and BV13 and BV17 family members, respectively. This analysis may be useful in designing an array of clinically useful homologous peptides with optimal MHC binding properties and highly cross-reactive TCR binding motifs.",
keywords = "Network regulation, TCR peptide vaccination, V gene epitopes",
author = "Arthur Vandenbark and Nicole Culbertson and Tom Finn and David Barnes and Abigail Buenafe and Burrows, {Gregory G.} and Sandra Law and Chou, {Yuan K.} and Halina Offner",
year = "2000",
language = "English (US)",
volume = "20",
pages = "57--83",
journal = "Critical Reviews in Immunology",
issn = "1040-8401",
publisher = "Begell House Inc.",
number = "1",

}

TY - JOUR

T1 - Human TCR as antigen

T2 - Homologies and potentially cross- reactive HLA-DR2-restricted epitopes within the AV and BV CDR2 loops

AU - Vandenbark, Arthur

AU - Culbertson, Nicole

AU - Finn, Tom

AU - Barnes, David

AU - Buenafe, Abigail

AU - Burrows, Gregory G.

AU - Law, Sandra

AU - Chou, Yuan K.

AU - Offner, Halina

PY - 2000

Y1 - 2000

N2 - The major function of the T-cell receptor is to confer antigen specificity to T cells. However, nascent TCR proteins that are not assembled into functional heterodimers may be processed and displayed with self MHC molecules on the T-cell surface, and are thought to be the genesis of autoregulatory T cells that can limit inflammatory responses through T-T network interactions. In previous work, we and others have exploited this natural regulatory system using TCR peptides to amplify regulatory T cells that potentially can treat human autoimmune diseases such as multiple sclerosis (MS) and arthritis. The development of this approach is limited by the diversity of human TCR V gene sequences, and by lack of knowledge of exactly which regions of the V gene proteins are immunogenic in association with various MHC alleles. To identify similar amino acid sequences within and among human V gene families that might have immunologic cross reactivity, we aligned 74 known AV and 109 known BV protein sequences into homologous groups using the ClustalX program. Moreover, with a focus on CDR2 peptides that have previously been used to induce regulatory T cells in clinical trials, we established homologous peptide groups, and then identified the optimal amino acid motifs for binding to two alleles, HLA-DRB1*1501 and DRB5*0101, that have been associated with susceptibility to MS. From this analysis, > 75% of AV and BV CDR2 sequences were predicted to bind with at least moderate avidity to each of the DR2 alleles, thus enhancing the likelihood that they could be antigenic. Further ordering of putative TCR contact residues revealed a different set of homology groupings, including many intrafamily sequence matches and some interfamily matches that might allow immunological cross reactivity. Particularly striking were DRB1*1501-restricted IH-S and IY-S motifs shared by BV11, BV12, and BV13 and BV3, BV12, BV13, and BV17 family members, respectively, and DRB5*0101-restricted RL-H and RL-Y motifs shared by BV11, BV12, and BV13 and BV13 and BV17 family members, respectively. This analysis may be useful in designing an array of clinically useful homologous peptides with optimal MHC binding properties and highly cross-reactive TCR binding motifs.

AB - The major function of the T-cell receptor is to confer antigen specificity to T cells. However, nascent TCR proteins that are not assembled into functional heterodimers may be processed and displayed with self MHC molecules on the T-cell surface, and are thought to be the genesis of autoregulatory T cells that can limit inflammatory responses through T-T network interactions. In previous work, we and others have exploited this natural regulatory system using TCR peptides to amplify regulatory T cells that potentially can treat human autoimmune diseases such as multiple sclerosis (MS) and arthritis. The development of this approach is limited by the diversity of human TCR V gene sequences, and by lack of knowledge of exactly which regions of the V gene proteins are immunogenic in association with various MHC alleles. To identify similar amino acid sequences within and among human V gene families that might have immunologic cross reactivity, we aligned 74 known AV and 109 known BV protein sequences into homologous groups using the ClustalX program. Moreover, with a focus on CDR2 peptides that have previously been used to induce regulatory T cells in clinical trials, we established homologous peptide groups, and then identified the optimal amino acid motifs for binding to two alleles, HLA-DRB1*1501 and DRB5*0101, that have been associated with susceptibility to MS. From this analysis, > 75% of AV and BV CDR2 sequences were predicted to bind with at least moderate avidity to each of the DR2 alleles, thus enhancing the likelihood that they could be antigenic. Further ordering of putative TCR contact residues revealed a different set of homology groupings, including many intrafamily sequence matches and some interfamily matches that might allow immunological cross reactivity. Particularly striking were DRB1*1501-restricted IH-S and IY-S motifs shared by BV11, BV12, and BV13 and BV3, BV12, BV13, and BV17 family members, respectively, and DRB5*0101-restricted RL-H and RL-Y motifs shared by BV11, BV12, and BV13 and BV13 and BV17 family members, respectively. This analysis may be useful in designing an array of clinically useful homologous peptides with optimal MHC binding properties and highly cross-reactive TCR binding motifs.

KW - Network regulation

KW - TCR peptide vaccination

KW - V gene epitopes

UR - http://www.scopus.com/inward/record.url?scp=0034037418&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034037418&partnerID=8YFLogxK

M3 - Article

VL - 20

SP - 57

EP - 83

JO - Critical Reviews in Immunology

JF - Critical Reviews in Immunology

SN - 1040-8401

IS - 1

ER -