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Genetic and Structural Basis for Selection of a Ubiquitous T Cell Receptor Deployed in Epstein-Barr Virus Infection


Despite the ∼1018 αβ T cell receptor (TCR) structures that can be randomly manufactured by the human thymus, some surface more frequently than others. The pinnacles of this distortion are public TCRs, which exhibit amino acid-identical structures across different individuals. Public TCRs are thought to result from both recombinatorial bias and antigen-driven selection, but the mechanisms that underlie inter-individual TCR sharing are still largely theoretical. To examine this phenomenon at the atomic level, we solved the co-complex structure of one of the most widespread and numerically frequent public TCRs in the human population. The archetypal AS01 public TCR recognizes an immunodominant BMLF1 peptide, derived from the ubiquitous Epstein-Barr virus, bound to HLA-A*0201. The AS01 TCR was observed to dock in a diagonal fashion, grasping the solvent exposed peptide crest with two sets of complementarity-determining region (CDR) loops, and was fastened to the peptide and HLA-A*0201 platform with residue sets found only within TCR genes biased in the public response. Computer simulations of a random V(D)J recombination process demonstrated that both TCRα and TCRβ amino acid sequences could be manufactured easily, thereby explaining the prevalence of this receptor across different individuals. Interestingly, the AS01 TCR was encoded largely by germline DNA, indicating that the TCR loci already comprise gene segments that specifically recognize this ancient pathogen. Such pattern recognition receptor-like traits within the αβ TCR system further blur the boundaries between the adaptive and innate immune systems.


Vyšlo v časopise: Genetic and Structural Basis for Selection of a Ubiquitous T Cell Receptor Deployed in Epstein-Barr Virus Infection. PLoS Pathog 6(11): e32767. doi:10.1371/journal.ppat.1001198
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001198

Souhrn

Despite the ∼1018 αβ T cell receptor (TCR) structures that can be randomly manufactured by the human thymus, some surface more frequently than others. The pinnacles of this distortion are public TCRs, which exhibit amino acid-identical structures across different individuals. Public TCRs are thought to result from both recombinatorial bias and antigen-driven selection, but the mechanisms that underlie inter-individual TCR sharing are still largely theoretical. To examine this phenomenon at the atomic level, we solved the co-complex structure of one of the most widespread and numerically frequent public TCRs in the human population. The archetypal AS01 public TCR recognizes an immunodominant BMLF1 peptide, derived from the ubiquitous Epstein-Barr virus, bound to HLA-A*0201. The AS01 TCR was observed to dock in a diagonal fashion, grasping the solvent exposed peptide crest with two sets of complementarity-determining region (CDR) loops, and was fastened to the peptide and HLA-A*0201 platform with residue sets found only within TCR genes biased in the public response. Computer simulations of a random V(D)J recombination process demonstrated that both TCRα and TCRβ amino acid sequences could be manufactured easily, thereby explaining the prevalence of this receptor across different individuals. Interestingly, the AS01 TCR was encoded largely by germline DNA, indicating that the TCR loci already comprise gene segments that specifically recognize this ancient pathogen. Such pattern recognition receptor-like traits within the αβ TCR system further blur the boundaries between the adaptive and innate immune systems.


Zdroje

1. ElliottSL

SuhrbierA

MilesJJ

LawrenceG

PyeSJ

2008

Phase I trial of a CD8+ T-cell peptide epitope-based vaccine for infectious mononucleosis.

J Virol

82

1448

1457

2. MacsweenKF

CrawfordDH

2003

Epstein-Barr virus-recent advances.

Lancet Infect Dis

3

131

140

3. KhanN

HislopA

GudgeonN

CobboldM

KhannaR

2004

Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection.

J Immunol

173

7481

7489

4. HislopAD

AnnelsNE

GudgeonNH

LeeseAM

RickinsonAB

2002

Epitope-specific evolution of human CD8(+) T cell responses from primary to persistent phases of Epstein-Barr virus infection.

J Exp Med

195

893

905

5. TrautmannL

LabarriereN

JotereauF

KaranikasV

GervoisN

2002

Dominant TCR V alpha usage by virus and tumor-reactive T cells with wide affinity ranges for their specific antigens.

Eur J Immunol

32

3181

3190

6. AnnelsNE

CallanMF

TanL

RickinsonAB

2000

Changing patterns of dominant TCR usage with maturation of an EBV-specific cytotoxic T cell response.

J Immunol

165

4831

4841

7. LimA

TrautmannL

PeyratMA

CouedelC

DavodeauF

2000

Frequent contribution of T cell clonotypes with public TCR features to the chronic response against a dominant EBV-derived epitope: application to direct detection of their molecular imprint on the human peripheral T cell repertoire.

J Immunol

165

2001

2011

8. PriceDA

BrenchleyJM

RuffLE

BettsMR

HillBJ

2005

Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses.

J Exp Med

202

1349

1361

9. IancuEM

CorthesyP

BaumgaertnerP

DevevreE

VoelterV

2009

Clonotype selection and composition of human CD8 T cells specific for persistent herpes viruses varies with differentiation but is stable over time.

J Immunol

183

319

331

10. CabaniolsJP

FazilleauN

CasrougeA

KourilskyP

KanellopoulosJM

2001

Most alpha/beta T cell receptor diversity is due to terminal deoxynucleotidyl transferase.

J Exp Med

194

1385

1390

11. DavisMM

BjorkmanPJ

1988

T-cell antigen receptor genes and T-cell recognition.

Nature

334

395

402

12. LieberMR

1991

Site-specific recombination in the immune system.

Faseb J

5

2934

2944

13. ShortmanK

EgertonM

SpangrudeGJ

ScollayR

1990

The generation and fate of thymocytes.

Semin Immunol

2

3

12

14. ArstilaTP

CasrougeA

BaronV

EvenJ

KanellopoulosJ

1999

A direct estimate of the human alphabeta T cell receptor diversity.

Science

286

958

961

15. TurnerSJ

DohertyPC

McCluskeyJ

RossjohnJ

2006

Structural determinants of T-cell receptor bias in immunity.

Nat Rev Immunol

6

883

894

16. MilesJJ

BrennanRM

BurrowsSR

2009

T cell receptor bias in humans.

Current Immunology Reviews

5

10

21

17. VenturiV

ChinHY

AsherTE

LadellK

ScheinbergP

2008

TCR beta-chain sharing in human CD8+ T cell responses to cytomegalovirus and EBV.

J Immunol

181

7853

7862

18. TickleIJ

LaskowskiRA

MossDS

2000

Rfree and the rfree ratio. II. Calculation Of the expected values and variances of cross-validation statistics in macromolecular least-squares refinement.

Acta Crystallogr D Biol Crystallogr

56

442

450

19. RudolphMG

StanfieldRL

WilsonIA

2006

How TCRs bind MHCs, peptides, and coreceptors.

Annu Rev Immunol

24

419

466

20. GrasS

SaulquinX

ReiserJB

DebeaupuisE

EchasserieauK

2009

Structural bases for the affinity-driven selection of a public TCR against a dominant human cytomegalovirus epitope.

J Immunol

183

430

437

21. ColeDK

YuanF

RizkallahPJ

MilesJJ

GostickE

2009

Germ line-governed recognition of a cancer epitope by an immunodominant human T-cell receptor.

J Biol Chem

284

27281

27289

22. ArchboldJK

MacdonaldWA

GrasS

ElyLK

MilesJJ

2009

Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition.

J Exp Med

206

209

219

23. TynanFE

BurrowsSR

BuckleAM

ClementsCS

BorgNA

2005

T cell receptor recognition of a ‘super-bulged’ major histocompatibility complex class I-bound peptide.

Nat Immunol

6

1114

1122

24. ColeDK

PumphreyNJ

BoulterJM

SamiM

BellJI

2007

Human TCR-binding affinity is governed by MHC class restriction.

J Immunol

178

5727

5734

25. Varela-RohenaA

MolloyPE

DunnSM

LiY

SuhoskiMM

2008

Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor.

Nat Med

14

1390

1395

26. van der MerwePA

DavisSJ

2003

Molecular interactions mediating T cell antigen recognition.

Annu Rev Immunol

21

659

684

27. ArmstrongKM

InsaidooFK

BakerBM

2008

Thermodynamics of T-cell receptor-peptide/MHC interactions: progress and opportunities.

J Mol Recognit

21

275

287

28. CCP4

1994

The Collaborative Computational Project Number 4, suite programs for protein crystallography.

Acta Cryst

d50

760

763

29. VenturiV

PriceDA

DouekDC

DavenportMP

2008

The molecular basis for public T-cell responses?

Nat Rev Immunol

8

231

238

30. VenturiV

KedzierskaK

PriceDA

DohertyPC

DouekDC

2006

Sharing of T cell receptors in antigen-specific responses is driven by convergent recombination.

Proc Natl Acad Sci U S A

103

18691

18696

31. VenturiV

ChinHY

PriceDA

DouekDC

DavenportMP

2008

The role of production frequency in the sharing of simian immunodeficiency virus-specific CD8+ TCRs between macaques.

J Immunol

181

2597

2609

32. RobinsonJ

WallerMJ

ParhamP

de GrootN

BontropR

2003

IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex.

Nucleic Acids Res

31

311

314

33. HislopAD

TaylorGS

SauceD

RickinsonAB

2007

Cellular responses to viral infection in humans: lessons from Epstein-Barr virus.

Annu Rev Immunol

25

587

617

34. BurrowsSR

ChenZ

ArchboldJK

TynanFE

BeddoeT

Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability.

Proc Natl Acad Sci U S A

107

10608

10613

35. WillcoxBE

GaoGF

WyerJR

LadburyJE

BellJI

1999

TCR binding to peptide-MHC stabilizes a flexible recognition interface.

Immunity

10

357

365

36. BonifaceJJ

ReichZ

LyonsDS

DavisMM

1999

Thermodynamics of T cell receptor binding to peptide-MHC: evidence for a general mechanism of molecular scanning.

Proc Natl Acad Sci U S A

96

11446

11451

37. DavisSJ

IkemizuS

EvansEJ

FuggerL

BakkerTR

2003

The nature of molecular recognition by T cells.

Nat Immunol

4

217

224

38. TheodossisA

GuillonneauC

WellandA

ElyLK

ClementsCS

Constraints within major histocompatibility complex class I restricted peptides: presentation and consequences for T-cell recognition.

Proc Natl Acad Sci U S A

107

5534

5539

39. ZengMS

LiDJ

LiuQL

SongLB

LiMZ

2005

Genomic sequence analysis of Epstein-Barr virus strain GD1 from a nasopharyngeal carcinoma patient.

J Virol

79

15323

15330

40. DolanA

AddisonC

GathererD

DavisonAJ

McGeochDJ

2006

The genome of Epstein-Barr virus type 2 strain AG876.

Virology

350

164

170

41. BellMJ

BrennanR

MilesJJ

MossDJ

BurrowsJM

2008

Widespread sequence variation in Epstein-Barr virus nuclear antigen 1 influences the antiviral T cell response.

J Infect Dis

197

1594

1597

42. DuraiswamyJ

BurrowsJM

BharadwajM

BurrowsSR

CooperL

2003

Ex vivo analysis of T-cell responses to Epstein-Barr virus-encoded oncogene latent membrane protein 1 reveals highly conserved epitope sequences in virus isolates from diverse geographic regions.

J Virol

77

7401

7410

43. MidgleyRS

BellAI

YaoQY

Croom-CarterD

HislopAD

2003

HLA-A11-restricted epitope polymorphism among Epstein-Barr virus strains in the highly HLA-A11-positive Chinese population: incidence and immunogenicity of variant epitope sequences.

J Virol

77

11507

11516

44. NagamineM

TakaharaM

KishibeK

NagatoT

IshiiH

2007

Sequence variations of Epstein-Barr virus LMP1 gene in nasal NK/T-cell lymphoma.

Virus Genes

34

47

54

45. KhannaR

SladeRW

PoulsenL

MossDJ

BurrowsSR

1997

Evolutionary dynamics of genetic variation in Epstein-Barr virus isolates of diverse geographical origins: evidence for immune pressure-independent genetic drift.

J Virol

71

8340

8346

46. Hutt-FletcherLM

2007

Epstein-Barr virus entry.

J Virol

81

7825

7832

47. Kjer-NielsenL

ClementsCS

PurcellAW

BrooksAG

WhisstockJC

2003

A structural basis for the selection of dominant alphabeta T cell receptors in antiviral immunity.

Immunity

18

53

64

48. Stewart-JonesGB

McMichaelAJ

BellJI

StuartDI

JonesEY

2003

A structural basis for immunodominant human T cell receptor recognition.

Nat Immunol

4

657

663

49. ArgaetVP

SchmidtCW

BurrowsSR

SilinsSL

KurillaMG

1994

Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein-Barr virus.

J Exp Med

180

2335

2340

50. BorgNA

ElyLK

BeddoeT

MacdonaldWA

ReidHH

2005

The CDR3 regions of an immunodominant T cell receptor dictate the ‘energetic landscape’ of peptide-MHC recognition.

Nat Immunol

6

171

180

51. BurrowsSR

SilinsSL

MossDJ

KhannaR

MiskoIS

1995

T cell receptor repertoire for a viral epitope in humans is diversified by tolerance to a background major histocompatibility complex antigen.

J Exp Med

182

1703

1715

52. LehnerPJ

WangEC

MossPA

WilliamsS

PlattK

1995

Human HLA-A0201-restricted cytotoxic T lymphocyte recognition of influenza A is dominated by T cells bearing the V beta 17 gene segment.

J Exp Med

181

79

91

53. MossPA

MootsRJ

RosenbergWM

Rowland-JonesSJ

BodmerHC

1991

Extensive conservation of alpha and beta chains of the human T-cell antigen receptor recognizing HLA-A2 and influenza A matrix peptide.

Proc Natl Acad Sci U S A

88

8987

8990

54. IshizukaJ

Stewart-JonesGB

van der MerweA

BellJI

McMichaelAJ

2008

The structural dynamics and energetics of an immunodominant T cell receptor are programmed by its Vbeta domain.

Immunity

28

171

182

55. LantzO

BendelacA

1994

An invariant T cell receptor alpha chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-8- T cells in mice and humans.

J Exp Med

180

1097

1106

56. BorgNA

WunKS

Kjer-NielsenL

WilceMC

PellicciDG

2007

CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor.

Nature

448

44

49

57. Scott-BrowneJP

MatsudaJL

MallevaeyT

WhiteJ

BorgNA

2007

Germline-encoded recognition of diverse glycolipids by natural killer T cells.

Nat Immunol

8

1105

1113

58. PellicciDG

PatelO

Kjer-NielsenL

PangSS

SullivanLC

2009

Differential recognition of CD1d-alpha-galactosyl ceramide by the V beta 8.2 and V beta 7 semi-invariant NKT T cell receptors.

Immunity

31

47

59

59. DavisonAJ

2002

Evolution of the herpesviruses.

Vet Microbiol

86

69

88

60. RothDB

2000

From lymphocytes to sharks: V(D)J recombinase moves to the germline.

Genome Biol

1

REVIEWS1014

61. GarciaKC

AdamsJJ

FengD

ElyLK

2009

The molecular basis of TCR germline bias for MHC is surprisingly simple.

Nat Immunol

10

143

147

62. AlemsegedZ

CoppensY

GeraadsD

2002

Hominid cranium from Omo: Description and taxonomy of Omo-323-1976-896.

Am J Phys Anthropol

117

103

112

63. LaugelB

van den BergHA

GostickE

ColeDK

WooldridgeL

2007

Different T cell receptor affinity thresholds and CD8 coreceptor dependence govern cytotoxic T lymphocyte activation and tetramer binding properties.

J Biol Chem

282

23799

23810

64. PanzaraMA

GussoniE

SteinmanL

OksenbergJR

1992

Analysis of the T cell repertoire using the PCR and specific oligonucleotide primers.

Biotechniques

12

728

735

65. LefrancMP

2003

IMGT, the international ImMunoGeneTics database.

Nucleic Acids Res

31

307

310

66. GarbocziDN

GhoshP

UtzU

FanQR

BiddisonWE

1996

Structure of the complex between human T-cell receptor, viral peptide and HLA-A2.

Nature

384

134

141

67. BoulterJM

GlickM

TodorovPT

BastonE

SamiM

2003

Stable, soluble T-cell receptor molecules for crystallization and therapeutics.

Protein Eng

16

707

711

68. WyerJR

WillcoxBE

GaoGF

GerthUC

DavisSJ

1999

T cell receptor and coreceptor CD8 alphaalpha bind peptide-MHC independently and with distinct kinetics.

Immunity

10

219

225

69. ElyLK

BeddoeT

ClementsCS

MatthewsJM

PurcellAW

2006

Disparate thermodynamics governing T cell receptor-MHC-I interactions implicate extrinsic factors in guiding MHC restriction.

Proc Natl Acad Sci U S A

103

6641

6646

70. LeslieAGW

1992

Recent changes to the MOSFLM package for processing film and image plate data Joint CCP4 + ESF-EAMCB Newsletter on Protein Crystallography

26

71. TrapaniS

NavazaJ

2008

AMoRe: classical and modern.

Acta Crystallogr D Biol Crystallogr

64

11

16

72. EmsleyP

CowtanK

2004

Coot: model-building tools for molecular graphics.

Acta Crystallogr D Biol Crystallogr

60

2126

2132

73. MurshudovGN

VaginAA

DodsonEJ

1997

Refinement of macromolecular structures by the maximum-likelihood method.

Acta Crystallogr D Biol Crystallogr

53

240

255

74. DelanoWL

2002

The PyMOL Molecular Graphics System.

San Carlos, CA, USA

DeLano Scientific

75. DingYH

SmithKJ

GarbocziDN

UtzU

BiddisonWE

1998

Two human T cell receptors bind in a similar diagonal mode to the HLA-A2/Tax peptide complex using different TCR amino acids.

Immunity

8

403

411

76. ChenJL

Stewart-JonesG

BossiG

LissinNM

WooldridgeL

2005

Structural and kinetic basis for heightened immunogenicity of T cell vaccines.

J Exp Med

201

1243

1255

77. TynanFE

ReidHH

Kjer-NielsenL

MilesJJ

WilceMC

2007

A T cell receptor flattens a bulged antigenic peptide presented by a major histocompatibility complex class I molecule.

Nat Immunol

8

268

276

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