Protective Efficacy of Cross-Reactive CD8 T Cells Recognising Mutant Viral Epitopes Depends on Peptide-MHC-I Structural Interactions and T Cell Activation Threshold

English version České info

Emergence of a new influenza strain leads to a rapid global spread of the virus due to minimal antibody immunity. Pre-existing CD8⁺ T-cell immunity directed towards conserved internal viral regions can greatly ameliorate the disease. However, mutational escape within the T cell epitopes is a substantial issue for virus control and vaccine design. Although mutations can result in a loss of T cell recognition, some variants generate cross-reactive T cell responses. In this study, we used reverse genetics to modify the influenza NP_336–374 peptide at a partially-solvent exposed residue (N->A, NPN3A mutation) to assess the availability, effectiveness and mechanism underlying influenza-specific cross-reactive T cell responses. The engineered virus induced a diminished CD8⁺ T cell response and selected a narrowed T cell receptor (TCR) repertoire within two Vβ regions (Vβ8.3 and Vβ9). This can be partially explained by the H-2D^bNPN3A structure that showed a loss of several contacts between the NPN3A peptide and H-2D^b, including a contact with His155, a position known to play an important role in mediating TCR-pMHC-I interactions. Despite these differences, common cross-reactive TCRs were detected in both the naïve and immune NPN3A-specific TCR repertoires. However, while the NPN3A epitope primes memory T-cells that give an equivalent recall response to the mutant or wild-type (wt) virus, both are markedly lower than wt->wt challenge. Such decreased CD8⁺ responses elicited after heterologous challenge resulted in delayed viral clearance from the infected lung. Furthermore, mice first exposed to the wt virus give a poor, low avidity response following secondary infection with the mutant. Thus, the protective efficacy of cross-reactive CD8⁺ T cells recognising mutant viral epitopes depend on peptide-MHC-I structural interactions and functional avidity. Our study does not support vaccine strategies that include immunization against commonly selected cross-reactive variants with mutations at partially-solvent exposed residues that have characteristics comparable to NPN3A.

Vyšlo v časopise: Protective Efficacy of Cross-Reactive CD8 T Cells Recognising Mutant Viral Epitopes Depends on Peptide-MHC-I Structural Interactions and T Cell Activation Threshold. PLoS Pathog 6(8): e32767. doi:10.1371/journal.ppat.1001039
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001039

Souhrn

Zdroje

1. DohertyPC

TurnerSJ

WebbyRG

ThomasPG

2006 Influenza and the challenge for immunology. Nat Immunol 7 449 455

2. ThomasPG

BrownSA

KeatingR

YueW

MorrisMY

2007 Hidden epitopes emerge in secondary influenza virus-specific CD8+ T cell responses. J Immunol 178 3091 3098

3. PircherH

MoskophidisD

RohrerU

BurkiK

HengartnerH

1990 Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo. Nature 346 629 633

4. MooreC

JohnM

JamesI

ChristiansenF

WittC

2002 Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science 296 1439 1443

5. PriceDA

WestSM

BettsMR

RuffLE

BrenchleyJM

2004 T cell receptor recognition motifs govern immune escape patterns in acute SIV infection. Immunity 21 793 803

6. FernandezC

StratovI

De RoseR

WalshK

DaleC

2005 Rapid viral escape at an immunodominant simian-human immunodeficiency virus cytotoxic T-lymphocyte epitope exacts a dramatic fitness cost. J Virol 79 5721 5731

7. Neumann-HaefelinC

McKiernanS

WardS

ViazovS

SpangenbergHC

2006 Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution. Hepatology 43 563 572

8. ButlerNS

TheodossisA

WebbAI

DunstoneMA

NastovskaR

2008 Structural and Biological Basis of CTL Escape in Coronavirus-Infected Mice. J Immunol 180 3926 3937

9. ButlerNS

TheodossisA

WebbAI

NastovskaR

RamarathinamSH

2008 Prevention of cytotoxic T cell escape using a heteroclitic subdominant viral T cell determinant. PLoS Pathog 4 e1000186

10. TophamDJ

DohertyPC

1998 Clearance of an influenza A virus by CD4+ T cells is inefficient in the absence of B cells. J Virol 72 882 885

11. GogJ

RimmelzwaanG

OsterhausA

GrenfellB

2003 Population dynamics of rapid fixation in cytotoxic T lymphocyte escape mutants of influenza A. Proc Natl Acad Sci U S A 100 11143 11147

12. RimmelzwaanGF

BoonAC

VoetenJT

BerkhoffEG

FouchierRA

2004 Sequence variation in the influenza A virus nucleoprotein associated with escape from cytotoxic T lymphocytes. Virus Res 103 97 100

13. BoonAC

de MutsertG

GrausYM

FouchierRA

SintnicolaasK

2002 Sequence variation in a newly identified HLA-B35-restricted epitope in the influenza A virus nucleoprotein associated with escape from cytotoxic T lymphocytes. J Virol 76 2567 2572

14. VoetenJT

BestebroerTM

NieuwkoopNJ

FouchierRA

OsterhausAD

2000 Antigenic drift in the influenza A virus (H3N2) nucleoprotein and escape from recognition by cytotoxic T lymphocytes. J Virol 74 6800 6807

15. TanPT

HeinyAT

MiottoO

SalmonJ

MarquesET

2010 Conservation and diversity of influenza A H1N1 HLA-restricted T cell epitope candidates for epitope-based vaccines. PLoS One 5 e8754

16. RimmelzwaanGF

KreijtzJH

BodewesR

FouchierRA

OsterhausAD

2009 Influenza virus CTL epitopes, remarkably conserved and remarkably variable. Vaccine 27 6363 6365

17. BerkhoffEG

de WitE

Geelhoed-MierasMM

BoonAC

SymonsJ

2005 Functional constraints of influenza A virus epitopes limit escape from cytotoxic T lymphocytes. J Virol 79 11239 11246

18. WahlA

McCoyW

SchaferF

BardetW

BuchliR

2009 T-cell tolerance for variability in an HLA class I-presented influenza A virus epitope. J Virol 83 9206 9214

19. WahlA

SchaferF

BardetW

BuchliR

AirGM

2009 HLA class I molecules consistently present internal influenza epitopes. Proc Natl Acad Sci U S A 106 540 545

20. KedzierskaK

La GrutaNL

TurnerSJ

DohertyPC

2006 Establishment and recall of CD8+ T cell memory in a model of localized transient infection. Immunol Rev 211 133 145

21. TurnerSJ

KedzierskaK

KomodromouH

La GrutaNL

DunstoneMA

2005 Lack of prominent peptide-major histocompatibility complex features limits repertoire diversity in virus-specific CD8(+) T cell populations. Nat Immunol 6 382 389

22. KedzierskaK

GuillonneauC

GrasS

HattonLA

WebbyR

2008 Complete modification of TCR specificity and repertoire selection does not perturb a CD8+ T cell immunodominance hierarchy. Proc Natl Acad Sci U S A 105 19408 19413

23. YoungAC

ZhangW

SacchettiniJC

NathensonSG

1994 The three-dimensional structure of H-2Db at 2.4 A resolution: implications for antigen-determinant selection. Cell 76 39 50

24. BelzGT

WodarzD

DiazG

NowakMA

DohertyPC

2002 Compromised influenza virus-specific CD8(+)-T-cell memory in CD4(+)-T-cell-deficient mice. J Virol 76 12388 12393

25. BelzGT

StevensonPG

DohertyPC

2000 Contemporary analysis of MHC-related immunodominance hierarchies in the CD8+ T cell response to influenza A viruses. J Immunol 165 2404 2409

26. HouS

HylandL

RyanKW

PortnerA

DohertyPC

1994 Virus-specific CD8+ T-cell memory determined by clonal burst size. Nature 369 652 654

27. SallustoF

LenigD

ForsterR

LippM

LanzavecchiaA

1999 Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401 708 712

28. KaechSM

TanJT

WherryEJ

KoniecznyBT

SurhCD

2003 Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat Immunol 4 1191 1198

29. La GrutaNL

TurnerSJ

DohertyPC

2004 Hierarchies in cytokine expression profiles for acute and resolving influenza virus-specific CD8+ T cell responses: correlation of cytokine profile and TCR avidity. J Immunol 172 5553 5560

30. TheodossisA

GuillonneauC

WellandA

ElyLK

ClementsCS

2010 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

31. 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

32. GodfreyDI

RossjohnJ

McCluskeyJ

2008 The fidelity, occasional promiscuity, and versatility of T cell receptor recognition. Immunity 28 304 314

33. La GrutaNL

RothwellWT

CukalacT

SwanNG

ValkenburgSA

2010 Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion. J Clin Invest

34. KedzierskaK

TurnerSJ

DohertyPC

2004 Conserved T cell receptor usage in primary and recall responses to an immunodominant influenza virus nucleoprotein epitope. Proc Natl Acad Sci U S A 101 4942 4947

35. KedzierskaK

DayEB

PiJ

HeardSB

DohertyPC

2006 Quantification of Repertoire Diversity of Influenza-Specific Epitopes with Predominant Public or Private TCR Usage. J Immunol 177 6705 6712

36. ZhongW

DixitSB

MallisRJ

ArthanariH

LugovskoyAA

2007 CTL recognition of a protective immunodominant influenza A virus nucleoprotein epitope utilizes a highly restricted Vbeta but diverse Valpha repertoire: functional and structural implications. J Mol Biol 372 535 548

37. DeckhutAM

AllanW

McMickleA

EichelbergerM

BlackmanMA

1993 Prominent usage of V beta 8.3 T cells in the H-2Db-restricted response to an influenza A virus nucleoprotein epitope. J Immunol 151 2658 2666

38. WherryEJ

TeichgraberV

BeckerTC

MasopustD

KaechSM

2003 Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol 4 225 234

39. KedzierskaK

VenturiV

FieldK

DavenportMP

TurnerSJ

2006 Early establishment of diverse TCR profiles for influenza-specific CD62Lhi CD8+ memory T cells. Proc Natl Acad Sci U S A 103 9184 9189

40. KedzierskaK

VenturiV

ValkenburgSA

DavenportMP

TurnerSJ

2008 Homogenization of TCR Repertoires within Secondary CD62Lhigh and CD62Llow Virus-Specific CD8+ T Cell Populations. J Immunol 180 7938 7947

41. JabbariA

HartyJT

2006 Secondary memory CD8+ T cells are more protective but slower to acquire a central-memory phenotype. J Exp Med 203 919 932

42. MasopustD

HaSJ

VezysV

AhmedR

2006 Stimulation history dictates memory CD8 T cell phenotype: implications for prime-boost vaccination. J Immunol 177 831 839

43. WallaceME

BrydenM

CoseSC

ColesRM

SchumacherTN

2000 Junctional biases in the naive TCR repertoire control the CTL response to an immunodominant determinant of HSV-1. Immunity 12 547 556

44. KershGJ

MileyMJ

NelsonCA

GrakouiA

HorvathS

2001 Structural and functional consequences of altering a peptide MHC anchor residue. J Immunol 166 3345 3354

45. CluteSC

WatkinLB

CornbergM

NaumovYN

SullivanJL

2005 Cross-reactive influenza virus-specific CD8+ T cells contribute to lymphoproliferation in Epstein-Barr virus-associated infectious mononucleosis. J Clin Invest 115 3602 3612

46. WedemeyerH

MizukoshiE

DavisAR

BenninkJR

RehermannB

2001 Cross-reactivity between hepatitis C virus and Influenza A virus determinant-specific cytotoxic T cells. J Virol 75 11392 11400

47. UrbaniS

AmadeiB

FisicaroP

PilliM

MissaleG

2005 Heterologous T cell immunity in severe hepatitis C virus infection. J Exp Med 201 675 680

48. CornbergM

ChenAT

WilkinsonLA

BrehmMA

KimSK

2006 Narrowed TCR repertoire and viral escape as a consequence of heterologous immunity. J Clin Invest 116 1443 1456

49. AllanW

TabiZ

ClearyA

DohertyPC

1990 Cellular events in the lymph node and lung of mice with influenza. Consequences of depleting CD4+ T cells. J Immunol 144 3980 3986

50. HoffmannE

MahmoodK

YangC

WebsterR

GreenbergH

2002 Rescue of influenza B virus from eight plasmids. Proc Natl Acad Sci U S A 99 11411 11416

51. HolmbergK

MariathasanS

OhtekiT

OhashiPS

GascoigneNR

2003 TCR binding kinetics measured with MHC class I tetramers reveal a positive selecting peptide with relatively high affinity for TCR. J Immunol 171 2427 2434

52. SlifkaMK

WhittonJL

2001 Functional avidity maturation of CD8(+) T cells without selection of higher affinity TCR. Nat Immunol 2 711 717

53. MoonJJ

ChuHH

PepperM

McSorleySJ

JamesonSC

2007 Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27 203 213

54. CroweSR

TurnerSJ

MillerSC

RobertsAD

RappoloRA

2003 Differential antigen presentation regulates the changing patterns of CD8+ T cell immunodominance in primary and secondary influenza virus infections. J Exp Med 198 399 410

55. ClementsCS

Kjer-NielsenL

MacDonaldWA

BrooksAG

PurcellAW

2002 The production, purification and crystallization of a soluble heterodimeric form of a highly selected T-cell receptor in its unliganded and liganded state. Acta Crystallogr D Biol Crystallogr 58 2131 2134

56. MacdonaldW

WilliamsDS

ClementsCS

GormanJJ

Kjer-NielsenL

2002 Identification of a dominant self-ligand bound to three HLA B44 alleles and the preliminary crystallographic analysis of recombinant forms of each complex. FEBS Lett 527 27 32

57. KabschW

1993 Automatic processing of rotation diffraction data from crystals of initially unknown symmetry and cell constants. J Appl Cryst 26 795 800

58. McCoyAJ

Grosse-KunstleveRW

AdamsPD

WinnMD

StoroniLC

2007 Phaser Crystallographic Software. J Appl Cryst 40 658 674

59. 1994 The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr 50 760 763

60. JonesT

ZouJ

CowanS

KjeldgaardM

1991 Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr A 1991 110 119