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            Polymorphism, T Cell Avidity, and Diversity in Immune Defense

Messaoudi, Ilhem; Patiño, José A. Guevara; Dyall, Ruben; LeMaoult, Joël; Nikolich‐Žugich, Janko

doi:10.1126/science.1076064

Cited by 305 publications

(286 citation statements)

References 32 publications

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“…Higher TCR avidity has been proposed to be critical for the control of viral infections (50)(51)(52) or subsequent infections with related pathogens (40). Of note, we have also shown that the large TRB repertoire renewal observed after treatment interruption and Ag re-exposure may be associated with the increase of functional avidity of T cell recognition.…”

Section: Discussionsupporting

confidence: 55%

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

Miconnet

Marrau

Farina

et al. 2011

The Journal of Immunology

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Ex vivo analysis of virus-specific CD8 T cell populations by anchored PCR has shown that the CD8 TCR repertoire was less oligoclonal (seven to nine clonotypes per individual epitope) than previously thought. In the current study, TCR diversity was investigated by assessing both the overall TCR β-chain variable regions usage as well as the CDR3 regions in ex vivo-isolated CMV- and EBV-specific CD8 T cells from 27 healthy donors. The average number of clonotypes specific to most single viral epitopes comprised between 14 and 77. Changes in the CD8 TCR repertoire were also longitudinally assessed under conditions of HIV-1 chronic infection (i.e., in patients with suppressed virus replication and after treatment interruption and Ag re-exposure). The results showed that a large renewal (≤80%) of the TRB repertoire occurred after Ag re-exposure and was eventually associated with an increased T cell recognition functional avidity. These results demonstrate that the global CD8 TCR repertoire is much more diverse (≤9-fold) than previously estimated and provide the mechanistic basis for supporting massive repertoire renewal during chronic virus infection and Ag re-exposure.

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Section: Discussionsupporting

confidence: 55%

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

Miconnet

Marrau

Farina

et al. 2011

The Journal of Immunology

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“…After refolding with the mouse K d H and L chains, the peptide was able to bind with murine MHC class I molecules. MHC class I molecules, possessing high degrees of polymorphism as the result of the evolutionary process, are able to present various antigenic determinants to host T cells for induction of host immune responses to combat the invading foreign pathogens, such as viruses (32). The epitopes recognized by MHC molecules are believed to be between eight and 12 aa.…”

Section: Discussionmentioning

confidence: 99%

Generation of Murine CTL by a Hepatitis B Virus-Specific Peptide and Evaluation of the Adjuvant Effect of Heat Shock Protein Glycoprotein 96 and Its Terminal Fragments

Zhou

Han

et al. 2005

The Journal of Immunology

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Previously, we reported that a 7-mer HLA-A11-restricted peptide (YVNTNMG) of hepatitis B virus (HBV) core Ag (HBcAg88–94) was associated with heat shock protein (HSP) gp96 in liver tissues of patients with HBV-induced hepatocellular carcinoma (HCC). This peptide is highly homologous to a human HLA-A11-restricted 9-mer peptide (YVNVNMGLK) and to a mouse H-2-Kd-restricted 9-mer peptide (SYVNTNMGL). To further characterize its immunogenicity, BALB/c mice were vaccinated with the HBV 7-mer peptide. It was found that a specific CTL response was induced by the 7-mer peptide, although the response was ∼50% of that induced by the mouse H-2-Kd-restricted 9-mer peptide, as detected by ELISPOT, tetramer, and 51Cr release assays. To evaluate the adjuvant effect of HSP gp96, mice were coimmunized with gp96 and the 9-mer peptide, and a significant adjuvant effect was observed with gp96. To further determine whether the immune effect of gp96 was dependent on peptide binding, the N- and C-terminal fragments of gp96, which are believed to contain the putative peptide-binding domain, were cloned and expressed in Escherichia coli. CTL assays indicated that only the N-terminal fragment, but not the C-terminal fragment, was able to produce the adjuvant effect. These results clearly demonstrated the potential of using gp96 or its N-terminal fragment as a possible adjuvant to augment CTL response against HBV infection and HCC.

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“…These findings have important implications for designing vaccines aimed at promoting the magnitude and breadth of what are normally "minor" responses. This, in turn, may be advantageous for efficient viral clearance as well as the prevention of viral escape (4,5,53). The same arguments may apply to tumor immunity.…”

Section: Figurementioning

confidence: 94%

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

Gruta¹,

Rothwell²,

Cukalac³

et al. 2010

J. Clin. Invest.

145

211

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CD8 + T cell responses to viral infection are characterized by the emergence of dominant and subdominant CTL populations. The immunodominance hierarchies of these populations are highly reproducible for any given spectrum of virus-induced peptide-MHCI complexes and are likely determined by multiple factors. Recent studies demonstrate a direct correlation between naive epitope-specific CD8 + T cell precursor (CTLp) frequency and the magnitude of the response after antigen challenge. Thus, the number of available precursors in the naive pool has emerged as a key predictor of immunodominance. In contrast to this, we report here no consistent relationship between CTLp frequency and the subsequent magnitude of the immune response for 4 influenza virus-derived epitopes following intranasal infection of mice with influenza A virus. Rather, the characteristic, antigen-driven T cell immunodominance hierarchy was determined by the extent of recruitment from the available pool of epitope-specific precursors and the duration of their continued expansion over the course of the infection. These findings suggest possibilities for enhancing protective immune memory by maximizing both the size and diversity of typically subdominant T cell responses through rational vaccine design.

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Direct Link Between mhc Polymorphism, T Cell Avidity, and Diversity in Immune Defense

Cited by 305 publications

References 32 publications

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

Generation of Murine CTL by a Hepatitis B Virus-Specific Peptide and Evaluation of the Adjuvant Effect of Heat Shock Protein Glycoprotein 96 and Its Terminal Fragments

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

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