Sequence and Structural Analyses Reveal Distinct and Highly Diverse Human CD8 + TCR Repertoires to Immunodominant Viral Antigens

Chen, Guobing; Yang, Xinbo; Ko, Annette; Sun, Xiaoping; Gao, Mingming; Zhang, Yongqing; Shi, Alvin; Mariuzza, Roy A.; Weng, Nan‐ping

doi:10.1016/j.celrep.2017.03.072

Cited by 107 publications

(131 citation statements)

References 58 publications

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“…Thus, TCRβ repertoires were not dominated across the board by heavily conserved (public) sequences, in contrast to what was observed for some epitopes from influenza (51,52) or EBV (53). Rather, the TCRβ repertoires studied here were mostly composed of clonotypes that were shared with only a subset of matched donors, or were entirely donor-specific (private).…”

Section: Discussionmentioning

confidence: 62%

Antigen-specific T-cell receptor signatures of cytomegalovirus infection

Huth

Liang

Krebs

et al. 2018

Preprint

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Cytomegalovirus (CMV) is a prevalent human pathogen. The virus cannot be eliminated from the body, but is kept in check by CMV-specific T cells. Patients with an insufficient T-cell response, such as transplant recipients, are at high risk of developing CMV disease. However, 30 the CMV-specific T-cell repertoire is complex, and is not yet clear which T cells protect best against virus reactivation and disease. Here we present a highly resolved characterization of CMV-specific CD8+ T cells based on enrichment by specific peptide stimulation and mRNA sequencing of their T-cell receptor β chains (TCRβ). Our analysis included recently identified T-cell epitopes restricted through HLA-C, whose presentation is resistant to viral 35 immunomodulation, and well-studied HLA-B-restricted epitopes. In 8 healthy virus carriers, we identified a total of 1052 CMV-specific TCRβ chains. HLA-C-restricted, CMV-specific TCRβ clonotypes the ex vivo T-cell response, and contributed the highest-frequency clonotype of the entire repertoire in 2 of 8 donors. We analyzed sharing and similarity of CMV-specific TCRβ sequences and identified 63 public or related sequences belonging to 17 public TCRβ 40 families. In our cohort and in an independent cohort of 352 donors, the cumulative frequency of these public TCRβ family members was a highly discriminatory indicator of carrying both CMV infection and the relevant HLA type. Based on these findings, we propose CMV-specific TCRβ signatures as a biomarker for an antiviral T-cell response to identify patients in need of treatment and to guide future development of immunotherapy. 45

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Section: Discussionmentioning

confidence: 62%

Antigen-specific T-cell receptor signatures of cytomegalovirus infection

Huth

Liang

Krebs

et al. 2018

Preprint

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“…A previous study on antiviral TRA and TRB repertoires on CD8 + T cells suggested their relationship with immune protection. 36 Therefore, differentially expressed TRAs and TRBs could act in a coordinated manner during the pathogenesis of PBC.…”

Section: N This Study N-ras Was Upregulated In Cd4 + T Cells Of Pamentioning

confidence: 99%

CD4⁺ T cells from patients with primary biliary cholangitis show T cell activation and differentially expressed T‐cell receptor repertoires

Nakagawa

Muroyama

Saeki

et al. 2019

Hepatology Research

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Aim Primary biliary cholangitis (PBC) is an autoimmune liver disease with unknown pathogenesis. In PBC, activation of T‐cell receptor (TCR) signaling is associated with inflammatory cytokine production through N‐Ras upregulation. Although the CD4+ T cell TCR repertoire could be associated with PBC pathogenesis, it has not been evaluated. Thus, we analyzed the PBC‐CD4+ T cell TCR repertoire using next generation sequencing (NGS). Methods Four PBC patients (one treatment‐naïve and three receiving ursodeoxycholic acid) and three healthy individuals were enrolled. NRAS expression in CD4+ T cells was assessed by quantitative reverse transcription–polymerase chain reaction (qRT‐PCR). N‐Ras dynamics in CD4+ T cells were assessed by qRT‐PCR and GTP‐N‐Ras activation assay. The TCR α‐ (TRA) and β‐chain (TRB) repertoires on CD4+ T cells were analyzed by NGS and profiled using hierarchical analysis. Motif analysis was undertaken to elucidate the structure of PBC‐specific TCRs. Results NRAS was upregulated in PBC relative to control CD4+ T cells (P < 0.05), and N‐Ras enhanced T cell activation in CD4+ T cells. Among 2668 TRAs and 841 TRBs, 20 and 11, respectively, were differentially expressed in PBC compared to that in controls (P < 0.05, fold‐change >2). Among them, TRAV29/J22, TRBV6–5/J2–6, and TRBV10–1/J2–1 were expressed in PBC but the expression was negligible in the controls, with more mature and longer forms observed in PBC‐CD4+ T cells. Conclusions N‐Ras was upregulated in PBC‐CD4+ T cells, and it enhanced TCR activation, indicating that PBC‐CD4+ T cells were activated by N‐Ras upregulation with differentially expressed TCR repertoires on their surfaces.

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“…This implies that several peptides are recognized by the same TCR (cross‐reactivity), and conversely, that a single peptide can be recognized by several TCRs (promiscuity). More recent work using unique molecular identifier‐labelled high‐throughput sequencing and single T‐cell analysis of an HLA‐A2‐restricted CMVpp65 target (amino acids 495–503) showed that the diversity of TCRs recognizing a single epitope is far greater than expected . Several thousand TCR species recognized the same epitope, whereas TCRs against this single epitope represented about 3‐4% of the entire peripheral T‐cell pool.…”

Section: Homeostasis Of and Selection Pressure On Cmv‐directed T Cellsmentioning

confidence: 99%

“…More recent work using unique molecular identifierlabelled high-throughput sequencing and single T-cell analysis of an HLA-A2-restricted CMVpp65 target (amino acids 495-503) showed that the diversity of TCRs recognizing a single epitope is far greater than expected. 43,48 Several thousand TCR species recognized the same epitope, whereas TCRs against this single epitope represented about 3-4% of the entire peripheral T-cell pool. This study underlined that most T-cell analyses performed using T cells in peripheral circulation, which represent only about 2% of the entire lymphocyte pool [the remaining T cells (c. 98% of total) reside in organs and tissues], do not necessarily encompass the entire repertoire of CMV-specific TCRs.…”

Section: Homeostasis Of and Selection Pressure On Cmv-directed T Cellsmentioning

confidence: 99%

The impact of inflationary cytomegalovirus‐specific memory T cells on anti‐tumour immune responses in patients with cancer

et al. 2018

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Human cytomegalovirus (CMV) is a ubiquitous, persistent beta herpesvirus. CMV infection contributes to the accumulation of functional antigen-specific CD8 T-cell pools with an effector-memory phenotype and enrichment of these immune cells in peripheral organs. We review here this 'memory T-cell inflation' phenomenon and associated factors including age and sex. 'Collateral damage' due to CMV-directed immune reactivity may occur in later stages of life - arising from CMV-specific immune responses that were beneficial in earlier life. CMV may be considered an age-dependent immunomodulator and a double-edged sword in editing anti-tumour immune responses. Emerging evidence suggests that CMV is highly prevalent in patients with a variety of cancers, particularly glioblastoma. A better understanding of CMV-associated immune responses and its implications for immune senescence, especially in patients with cancer, may aid in the design of more clinically relevant and tailored, personalized treatment regimens. 'Memory T-cell inflation' could be applied in vaccine development strategies to enrich for immune reactivity where long-term immunological memory is needed, e.g. in long-term immune memory formation directed against transformed cells.

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Sequence and Structural Analyses Reveal Distinct and Highly Diverse Human CD8 + TCR Repertoires to Immunodominant Viral Antigens

Cited by 107 publications

References 58 publications

Antigen-specific T-cell receptor signatures of cytomegalovirus infection

Antigen-specific T-cell receptor signatures of cytomegalovirus infection

CD4⁺ T cells from patients with primary biliary cholangitis show T cell activation and differentially expressed T‐cell receptor repertoires

The impact of inflationary cytomegalovirus‐specific memory T cells on anti‐tumour immune responses in patients with cancer

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Sequence and Structural Analyses Reveal Distinct and Highly Diverse Human CD8 + TCR Repertoires to Immunodominant Viral Antigens

Cited by 107 publications

References 58 publications

Antigen-specific T-cell receptor signatures of cytomegalovirus infection

Antigen-specific T-cell receptor signatures of cytomegalovirus infection

CD4+ T cells from patients with primary biliary cholangitis show T cell activation and differentially expressed T‐cell receptor repertoires

The impact of inflationary cytomegalovirus‐specific memory T cells on anti‐tumour immune responses in patients with cancer

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CD4⁺ T cells from patients with primary biliary cholangitis show T cell activation and differentially expressed T‐cell receptor repertoires