Highly restricted T-cell receptor repertoire in the CD8+ T-cell response against an HIV-1 epitope with a stereotypic amino acid substitution

Miyazaki, Eriko; Kawana-Tachikawa, Ai; Tomizawa, Mariko; Nunoya, Jun-ichi; Odawara, Takashi; Fujii, Takeshi; Shi, Yi; Gao, George F.; Iwamoto, Aikichi

doi:10.1097/qad.0b013e32832605e6

Cited by 9 publications

(17 citation statements)

References 26 publications

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“…This smaller CD8 TCR repertoire is predominantly composed of memory cells, suggesting that older individuals may need to depend on crossreactive responses to any new pathogen (10). Narrowed TCR repertoires were previously shown for human persistent infections, such as those caused by Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis C virus, and HIV, where T cells are continuously exposed to antigen (11)(12)(13)(14). This could result from the selective antigen-driven proliferation of T cells with the better fit.…”

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confidence: 99%

Narrowing of Human Influenza A Virus-Specific T Cell Receptor α and β Repertoires with Increasing Age

Gil

Yassai

Naumov

et al. 2015

J Virol

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Alterations in memory CD8 T cell responses may contribute to the high morbidity and mortality caused by seasonal influenza A virus (IAV) infections in older individuals. We questioned whether memory CD8 responses to this nonpersistent virus, to which recurrent exposure with new strains is common, changed over time with increasing age. Here, we show a direct correlation between increasing age and narrowing of the HLA-A2-restricted IAV V␣ and V␤ T cell repertoires specific to M1 residues 58 to 66 (M1 58 -66 ), which simultaneously lead to oligoclonal expansions, including the usage of a single identical VA12-JA29 clonotype in all eight older donors. The V␣ repertoire of older individuals also had longer CDR3 regions with increased usage of G/A runs, whose molecular flexibility may enhance T cell receptor (TCR) promiscuity. Collectively, these results suggest that CD8 memory T cell responses to nonpersistent viruses like IAV in humans are dynamic, and with aging there is a reduced diversity but a preferential retention of T cell repertoires with features of enhanced crossreactivity. IMPORTANCEWith increasing age, the immune system undergoes drastic changes, and older individuals have declined resistance to infections. Vaccinations become less effective, and infection with influenza A virus in older individuals is associated with higher morbidity and mortality. Here, we questioned whether T cell responses directed against the highly conserved HLA-A2-restricted M1 58 -66 peptide of IAV evolves with increasing age. Specifically, we postulated that CD8 T cell repertoires narrow with recurrent exposure and may thus be less efficient in response to new infections with new strains of IAV. Detailed analyses of the VA and VB TCR repertoires simultaneously showed a direct correlation between increasing age and narrowing of the TCR repertoire. Features of the TCRs indicated potentially enhanced cross-reactivity in all older donors. In summary, T cell repertoire analysis in older individuals may be useful as one of the predictors of protection after vaccination. Remarkable progress in medicine combined with public health policy and socioeconomic development has resulted in longer life spans than ever before. It was predicted that in 2050 the proportion of people aged 65 years and older in the United States will more than double to 22% from the 10% in the year 2000 (1). This will present challenges and will have an impact on health care systems, and reversing the negative effects of aging would profit individuals and society. An age-related phenomenon known as "immunosenescence," where both innate and adaptive immune responses become impaired, can result in deleterious clinical endpoints (2). This process is linked to declining resistance to infections and the poor efficacy of vaccines in older individuals (3).Earlier reports have shown that T cell receptor (TCR) repertoire diversity is a key component of protection from infection (4-7). TCR gene sequences present unique markers for tracking T cell diversity. During agi...

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confidence: 99%

Narrowing of Human Influenza A Virus-Specific T Cell Receptor α and β Repertoires with Increasing Age

Gil

Yassai

Naumov

et al. 2015

J Virol

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“…We showed previously that TCR repertoire of the dual-specific CD8+ T cells was highly restricted14. TRBV4-1 and TRAV8-3 gene segments were used almost exclusively as TCR β and α chains, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…In an earlier study of pHLA/TCR interactions, we used double staining with Sendaivirus-derived pHLA-tetramers to differentiate three classes of CD8+ T cells in the peripheral mononuclear cells (PBMC) of HLA-A24-positive patients with chronic HIV-1 infection: Nef134-10(wt)-specific, Nef134-10(2F)-specific and dual-specific (reacting to both wt and 2F epitopes)1314. Since the encounter between TCR and pHLA is critical for CTL activation, structural studies examining the interactions between pHLA and TCR should be highly relevant in understanding the immune response to HIV-1 infection, including viral escape from immune surveillance.…”

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confidence: 99%

Structure of TCR and antigen complexes at an immunodominant CTL epitope in HIV-1 infection

Shimizu

Kawana-Tachikawa

Yamagata

et al. 2013

Sci Rep

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We investigated the crystal structure of an HLA-A*2402-restricted CTL epitope in the HIV-1 nef gene (Nef134-10) before (pHLA) or after TCR docking. The wild type epitope and two escape mutants were included in the study. Y135F was an early-appearing major mutation, while F139L was a late-appearing mutation which was selected in the patients without Y135F. F139 was an eminent feature of the Nef134-10 epitope. Wild type-specific TCR was less fit to F139L mutant suggesting that F139L is an escape from the CTL against the wild type epitope. Although Y135F mutation disrupted the hydrogen bond to HLA-A*2402 His70, newly formed hydrogen bond between T138 and His70 kept the conformation of the epitope in the reconstituted pMHC. TCR from Y135F- or dually-specific CTL had unique mode of binding to the mutant epitope. Y135F has been reported as a processing mutant but CTL carrying structurally adequate TCR can be found in the patients.

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“…We established Nef126-10 and Nef134-10-specific CTL clones, I30-1 and H27-9, as previously described [18]. CTL clones were cultured with RPMI 1640 supplemented with 50 U of interleukin-2/ml, 100U of penicillin/ml, 100U of streptomycin/ml, and 10% heat-inactivated FCS (R10/50), but the clones were cultured in the absence of interleukin-2 (R10) for two days before antigen presentation assays.…”

Section: Methodsmentioning

confidence: 99%

Switching and emergence of CTL epitopes in HIV-1 infection

et al. 2014

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BackgroundHuman Leukocyte Antigen (HLA) class I restricted Cytotoxic T Lymphocytes (CTLs) exert substantial evolutionary pressure on HIV-1, as evidenced by the reproducible selection of HLA-restricted immune escape mutations in the viral genome. An escape mutation from tyrosine to phenylalanine at the 135th amino acid (Y135F) of the HIV-1 nef gene is frequently observed in patients with HLA-A*24:02, an HLA Class I allele expressed in ~70% of Japanese persons. The selection of CTL escape mutations could theoretically result in the de novo creation of novel epitopes, however, the extent to which such dynamic “CTL epitope switching” occurs in HIV-1 remains incompletely known.ResultsTwo overlapping epitopes in HIV-1 nef, Nef126-10 and Nef134-10, elicit the most frequent CTL responses restricted by HLA-A*24:02. Thirty-five of 46 (76%) HLA-A*24:02-positive patients harbored the Y135F mutation in their plasma HIV-1 RNA. Nef codon 135 plays a crucial role in both epitopes, as it represents the C-terminal anchor for Nef126-10 and the N-terminal anchor for Nef134-10. While the majority of patients with 135F exhibited CTL responses to Nef126-10, none harboring the “wild-type” (global HIV-1 subtype B consensus) Y135 did so, suggesting that Nef126-10 is not efficiently presented in persons harboring Y135. Consistent with this, peptide binding and limiting dilution experiments confirmed F, but not Y, as a suitable C-terminal anchor for HLA-A*24:02. Moreover, experiments utilizing antigen specific CTL clones to recognize endogenously-expressed peptides with or without Y135F indicated that this mutation disrupted the antigen expression of Nef134-10. Critically, the selection of Y135F also launched the expression of Nef126-10, indicating that the latter epitope is created as a result of escape within the former.ConclusionsOur data represent the first example of the de novo creation of a novel overlapping CTL epitope as a direct result of HLA-driven immune escape in a neighboring epitope. The robust targeting of Nef126-10 following transmission (or in vivo selection) of HIV-1 containing Y135F may explain in part the previously reported stable plasma viral loads over time in the Japanese population, despite the high prevalence of both HLA-A*24:02 and Nef-Y135F in circulating HIV-1 sequences.

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Highly restricted T-cell receptor repertoire in the CD8+ T-cell response against an HIV-1 epitope with a stereotypic amino acid substitution

Abstract: These results provide an example of restricted TCR repertoire in a specific CTL response against the escaping epitope. We speculate that impairment of antigen presentation in escaping viruses may underlie the restricted repertoire.

Cited by 9 publications

References 26 publications

Narrowing of Human Influenza A Virus-Specific T Cell Receptor α and β Repertoires with Increasing Age

Narrowing of Human Influenza A Virus-Specific T Cell Receptor α and β Repertoires with Increasing Age

Structure of TCR and antigen complexes at an immunodominant CTL epitope in HIV-1 infection

Switching and emergence of CTL epitopes in HIV-1 infection

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