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1.
Immunol Cell Biol ; 88(2): 125-35, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19806163

RESUMO

Primary infection or recrudescence of latent virus infection in transplant recipients can be manifested either as asymptomatic or symptomatic disease. Here we show that symptomatic human cytomegalovirus (HCMV) or Epstein-Barr virus (EBV) infection or recrudescence following solid organ transplantation (SOT) was coincident with a dramatic skewing of T-cell receptor beta variable (TRBV) repertoire, with expansions of monoclonal/oligoclonal clonotypes. As the clinical symptoms resolved, the peripheral blood repertoire reverted to a more diverse distribution. In contrast, SOT recipients with asymptomatic or no viral infection or recrudescence showed minimal or no skewing of the T-cell receptor repertoire to maintain peripheral blood repertoire diversity. More importantly, we show that large monoclonal/oligoclonal repertoire expansions are associated with the loss of HCMV-specific T-cell function observed in SOT patients undergoing symptomatic viral infection or recrudescence, whereas SOT recipients who maintain peripheral blood TRBV repertoire diversity and functional antigen-specific T-cell responses can resist clinical symptomatic disease in spite of high levels of viral load.


Assuntos
Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Transplante de Órgãos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Adulto , Idoso , Proliferação de Células , Epitopos/imunologia , Humanos , Pessoa de Meia-Idade , Recidiva , Linfócitos T/citologia , Linfócitos T/virologia , Carga Viral
2.
Blood ; 111(8): 4283-92, 2008 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-18270323

RESUMO

CD8(+) T-cell responses to persistent viral infections are characterized by the accumulation of an oligoclonal T-cell repertoire and a reduction in the naive T-cell pool. However, the precise mechanism for this phenomenon remains elusive. Here we show that human cytomegalovirus (HCMV)-specific CD8(+) T cells recognizing distinct epitopes from the pp65 protein and restricted through an identical HLA class I allele (HLA B*3508) exhibited either a highly conserved public T-cell repertoire or a private, diverse T-cell response, which was uniquely altered in each donor following in vitro antigen exposure. Selection of a public T-cell receptor (TCR) was coincident with an atypical major histocompatibility complex (MHC)-peptide structure, in that the epitope adopted a helical conformation that bulged from the peptide-binding groove, while a diverse TCR profile was observed in response to the epitope that formed a flatter, more "featureless" landscape. Clonotypes with biased TCR usage demonstrated more efficient recognition of virus-infected cells, a greater CD8 dependency, and were more terminally differentiated in their phenotype when compared with the T cells expressing diverse TCR. These findings provide new insights into our understanding on how the biology of antigen presentation in addition to the structural features of the pMHC-I might shape the T-cell repertoire and its phenotype.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Peptídeos/imunologia , Alelos , Sequência de Aminoácidos , Anticorpos Monoclonais/imunologia , Antígenos Virais/imunologia , Sequência de Bases , Linhagem Celular , Células Clonais , Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/genética , Cristalografia por Raios X , Epitopos/imunologia , Antígenos HLA-B/imunologia , Humanos , Dados de Sequência Molecular , Peptídeos/química , Fenótipo , Receptores de Antígenos de Linfócitos T/imunologia
3.
J Virol ; 81(13): 7269-73, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17459926

RESUMO

Human cytomegalovirus (HCMV) elicits a very large burden on the immune system, with approximately one in ten T cells being reserved solely to manage this infection. However, information on the clonotypic composition of these vast T-cell populations is limited. In this study, we sequenced 116 T-cell receptor (TcR) alpha/beta-chains specific for the highly immunogenic HLA-B*3501-resticted epitope IPSINVHHY from the pp65 antigen. Interestingly, T cells recovered from all donors bore an identical or near-identical TRBV28/TRBJ1-4/TRAV17/TRAJ33 TcR. The ability to predict the responding alphabeta TcR repertoire before viral infection should prove a powerful tool for basic and clinical immunology.


Assuntos
Antígenos Virais/imunologia , Citomegalovirus/imunologia , Epitopos de Linfócito T/imunologia , Antígenos HLA-B/imunologia , Fosfoproteínas/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/imunologia , Proteínas da Matriz Viral/imunologia , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/imunologia , Antígenos HLA-B/sangue , Antígeno HLA-B35 , Humanos , Receptores de Antígenos de Linfócitos T alfa-beta/sangue
4.
J Immunol ; 177(10): 6804-14, 2006 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-17082594

RESUMO

The underlying generic properties of alphabeta TCRs that control MHC restriction remain largely unresolved. To investigate MHC restriction, we have examined the CTL response to a viral epitope that binds promiscuously to two human leukocyte Ags (HLAs) that differ by a single amino acid at position 156. Individuals expressing either HLA-B*3501 (156Leucine) or HLA-B*3508 (156Arginine) showed a potent CTL response to the 407HPVGEADYFEY417 epitope from EBV. Interestingly, the response was characterized by highly restricted TCR beta-chain usage in both HLA-B*3501+ and HLA-B*3508+ individuals; however, this conserved TRBV9+ beta-chain was associated with distinct TCR alpha-chains depending upon the HLA-B*35 allele expressed by the virus-exposed host. Functional assays confirmed that TCR alpha-chain usage determined the HLA restriction of the CTLs. Structural studies revealed significant differences in the mobility of the peptide when bound to HLA-B*3501 or HLA-B*3508. In HLA-B*3501, the bulged section of the peptide was disordered, whereas in HLA-B*3508 the bulged epitope adopted an ordered conformation. Collectively, these data demonstrate not only that mobile MHC-bound peptides can be highly immunogenic but can also stimulate an extremely biased TCR repertoire. In addition, TCR alpha-chain usage is shown to play a critical role in controlling MHC restriction between closely related allomorphs.


Assuntos
Epitopos de Linfócito T/metabolismo , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe I/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/virologia , Sequência de Aminoácidos , Apresentação de Antígeno/genética , Linhagem Celular Transformada , Células Cultivadas , Cristalografia por Raios X , Citotoxicidade Imunológica/genética , Epitopos de Linfócito T/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Antígenos HLA/imunologia , Antígenos HLA/metabolismo , Antígenos HLA-B/metabolismo , Antígeno HLA-B35 , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Dados de Sequência Molecular , Ligação Proteica/genética , Ligação Proteica/imunologia , Subunidades Proteicas/biossíntese , Subunidades Proteicas/genética , Subunidades Proteicas/fisiologia , Receptores de Antígenos de Linfócitos T alfa-beta/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/fisiologia , Linfócitos T Citotóxicos/imunologia
5.
Curr Med Chem ; 13(23): 2725-36, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17073624

RESUMO

T cell receptors are among the most specific biological structures found in nature and are therefore excellent candidates for the molecular targeting of antigen. It is becoming increasingly apparent that common sets of T cell receptors are frequently used in humans to combat pathogen and cancer derived threats. Given that many of these conserved T cell receptors have high affinity for their target ligands, there is potential to amass virtual banks of "off-the-shelf" receptors for use in a wide range of immunotherapeutic strategies. Additionally, such T cell receptors could become basic blueprints for artificial enhancement through mutagenesis, thereby creating an even better 3-dimensional fit for their cognate targets. Indeed, preliminary approaches using both "natural" and "supernatural" T cell receptors have shown promise in treating autoimmunity and malignancy. This review will discuss these studies and other approaches through which T cell receptors can be exploited in immunodiagnostics, pathogen control and gene therapy.


Assuntos
Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Terapia Genética , Humanos , Imunoterapia/métodos , Ligantes , Modelos Imunológicos , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/química
7.
J Immunol ; 175(6): 3826-34, 2005 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16148129

RESUMO

MHC class I molecules generally present peptides of 8-10 aa long, forming an extended coil in the HLA cleft. Although longer peptides can also bind to class I molecules, they tend to bulge from the cleft and it is not known whether the TCR repertoire has sufficient plasticity to recognize these determinants during the antiviral CTL response. In this study, we show that unrelated individuals infected with EBV generate a significant CTL response directed toward an HLA-B*3501-restricted, 11-mer epitope from the BZLF1 Ag. The 11-mer determinant adopts a highly bulged conformation with seven of the peptide side chains being solvent-exposed and available for TCR interaction. Such a complex potentially creates a structural challenge for TCR corecognition of both HLA-B*3501 and the peptide Ag. Surprisingly, unrelated B*3501 donors recognizing the 11-mer use identical or closely related alphabeta TCR sequences that share particular CDR3 motifs. Within the small number of dominant CTL clonotypes observed, each has discrete fine specificity for the exposed side chain residues of the peptide. The data show that bulged viral peptides are indeed immunogenic but suggest that the highly constrained TCR repertoire reflects a limit to TCR diversity when responding to some unusual MHC peptide ligands.


Assuntos
Apresentação de Antígeno , Antígenos Virais/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Citotóxicos/metabolismo , Antígenos Virais/química , Antígenos Virais/imunologia , Células Cultivadas , Proteínas de Ligação a DNA/imunologia , Epitopos de Linfócito T/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Antígenos HLA-B/imunologia , Antígeno HLA-B35 , Humanos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Conformação Proteica , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Transativadores/imunologia , Proteínas Virais/imunologia
8.
Nat Immunol ; 6(11): 1114-22, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16186824

RESUMO

Unusually long major histocompatibility complex (MHC) class I-restricted epitopes are important in immunity, but their 'bulged' conformation represents a potential obstacle to alphabeta T cell receptor (TCR)-MHC class I docking. To elucidate how such recognition is achieved while still preserving MHC restriction, we have determined here the structure of a TCR in complex with HLA-B(*)3508 presenting a peptide 13 amino acids in length. This complex was atypical of TCR-peptide-MHC class I interactions, being dominated at the interface by peptide-mediated interactions. The TCR assumed two distinct orientations, swiveling on top of the centrally bulged, rigid peptide such that only limited contacts were made with MHC class I. Although the TCR-peptide recognition resembled an antibody-antigen interaction, the TCR-MHC class I contacts defined a minimal 'generic footprint' of MHC-restriction. Thus our findings simultaneously demonstrate the considerable adaptability of the TCR and the 'shape' of MHC restriction.


Assuntos
Epitopos de Linfócito T/química , Antígenos HLA-B/química , Peptídeos/química , Receptores de Antígenos de Linfócitos T alfa-beta/química , Sequência de Aminoácidos , Apresentação de Antígeno , Linhagem Celular , Cristalografia por Raios X , Epitopos de Linfócito T/imunologia , Antígenos HLA-B/imunologia , Humanos , Dados de Sequência Molecular , Peptídeos/imunologia , Conformação Proteica , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T Citotóxicos/imunologia
9.
J Biol Chem ; 280(25): 23900-9, 2005 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-15849183

RESUMO

Although HLA class I alleles can bind epitopes up to 14 amino acids in length, little is known about the immunogenicity or the responding T-cell repertoire against such determinants. Here, we describe an HLA-B*3508-restricted cytotoxic T lymphocyte response to a 13-mer viral epitope (LPEPLPQGQLTAY). The rigid, centrally bulged epitope generated a biased T-cell response. Only the N-terminal face of the peptide bulge was critical for recognition by the dominant clonotype SB27. The SB27 public T-cell receptor (TcR) associated slowly onto the complex between the bulged peptide and the major histocompatibility complex, suggesting significant remodeling upon engagement. The broad antigen-binding cleft of HLA-B*3508 represents a critical feature for engagement of the public TcR, as the narrower binding cleft of HLA-B*3501(LPEPLPQGQLTAY), which differs from HLA-B*3508 by a single amino acid polymorphism (Arg156 --> Leu), interacted poorly with the dominant TcR. Biased TcR usage in this cytotoxic T lymphocyte response appears to reflect a dominant role of the prominent peptide x major histocompatibility complex class I surface.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Epitopos Imunodominantes/química , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Citotóxicos/imunologia , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular , Citometria de Fluxo , Humanos , Epitopos Imunodominantes/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular
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