Antigen-Driven Patterns of TCR Bias Are Shared across Diverse Outcomes of Human Hepatitis C Virus Infection

Miles, John J.; Thammanichanond, Duangtawan; Moneer, Sarah; Nivarthi, Usha K.; Tracy, Samantha Lilly; Aitken, Campbell; Brennan, Rebekah; Zeng, Weiguang; Marquart, Louise; Jackson, David C.; Burrows, Scott R.; Bowden, D. Scott; Torresi, Joseph; Hellard, Margaret; Rossjohn, Jamie; McCluskey, James; Bharadwaj, Mandvi

doi:10.4049/jimmunol.1003167

Cited by 25 publications

(24 citation statements)

References 32 publications

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“…33 In patients with hepatitis C virus (HCV) infection, Miles and colleagues observed that TCR repertoire diversity is associated with HCV clearance. 34 Hence, TCR diversity is associated with a greater likelihood of a competent immune recognition, which is not restricted to foreign pathogens, with important consequences for cancer immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

et al. 2018

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The role of T cell receptor (TCR) signaling for adaptive immune responses is essential. The ability to respond to a broad spectrum of tumor antigens requires an adaptive selection of various TCR. So far, little is known about the role of TCR richness and clonality in the cellular immune response to head and neck cancer (HNC), though the Endothelial Growth Factor Receptor (EGFR)-specific CD8+ T cell response can be enhanced by cetuximab therapy. Therefore, we investigated differences in TCR sequences between human papillomavirus (HPV)+ and HPV− HNC patients, as well as differences in TCR sequence characteristics between T cells of peripheral blood mononuclear cells (PBMC) and tumor infiltrating lymphocytes (TIL). Additionally, we were able to investigate the TCR richness and clonality in samples pre- and post- treatment in a prospective clinical trial of neoadjuvant cetuximab. Interestingly, HPV+ and HPV− HNSCC did not significantly differ in the extent of TCR clonality and richness in PBMC or TIL. However, neoadjuvant cetuximab treatment increased the number of unique TCR sequences in PBMC (p = 0.0003), which was more prominent in the clinical responder patients compared to non-responders (p = 0.04). A trend toward TCR gene focusing was observed in TIL (p = 0.1) post-treatment. Thus, an increase in richness of TCR sequences in the periphery with a focusing at the tumor site is associated with an improved treatment response, suggesting an influence of peripheral quantity and intratumoral quality on adaptive immunity in cetuximab treated patients.

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Section: Discussionmentioning

confidence: 99%

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

et al. 2018

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“…The structural study was based on an archetypal T cell line designated as DD31 generated from an HCV-infected subject (D#1) who primarily deployed TRBV11 clonotypes to engage HLA-B*0801-HSK and the functional study used HSK-specific polyclonal T cell lines from the same donor (D#1) and another HCV-infected, HLA-B*0801 + subject (D#2). The overall HSK-specific TCR repertoire has been previously published in Miles et al (13), in which D#1 and D#2 are designated as D#2 and D#5, respectively.…”

Section: Hsk and Its Natural Variants Stabilize Hla-b*0801 Equallymentioning

confidence: 99%

“…M (13). To assess the effect of these intergenotypic and quasispecies mutants on T cell recognition and function, peptides corresponding to the mutants were tested in functional assays using the HSK-specific T cell lines derived from D#1.…”

Section: Hsk-specific T Cells Are Cross-reactive To Intergenotypic Vamentioning

confidence: 99%

“…We recently compared the TCR repertoires selected against HLA-B*0801-HSK and a relatively conserved epitope HLA-A*0101-restricted 1435 ATDALMTGY 1443 in HCV-infected, HLAmatched subjects with diverse disease outcomes (natural HCV clearance versus persistent infection) and demonstrated that although a broad TCR repertoire was recruited against HLA-A*0101-1435 ATDALMTGY 1443 , the repertoire against HLA-B*0801-HSK was narrowly focused, with a strong bias towards the TCRb variable (TRBV) 11 gene family (13). TCR repertoire diversity and TCR bias can be influenced by a number of factors, including the avidity of the TCR to peptide-HLA (pHLA), the conformational characteristics of the peptide bound in the HLA groove, convergent recombination, thymic selection bias, Ag load, and clonal competition (14)(15)(16)(17)(18).…”

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confidence: 99%

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An Extensive Antigenic Footprint Underpins Immunodominant TCR Adaptability against a Hypervariable Viral Determinant

Nivarthi

Gras

Berry

et al. 2014

The Journal of Immunology

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Mutations in T cell epitopes are implicated in hepatitis C virus (HCV) persistence and can impinge on vaccine development. We recently demonstrated a narrow bias in the human TCR repertoire targeted at an immunodominant, but highly mutable, HLA-B*0801–restricted epitope (1395HSKKKCDEL1403 [HSK]). To investigate if the narrow TCR repertoire facilitates CTL escape, structural and biophysical studies were undertaken, alongside comprehensive functional analysis of T cells targeted at the natural variants of HLA-B*0801–HSK in different HCV genotypes and quasispecies. Interestingly, within the TCR–HLA-B*0801–HSK complex, the TCR contacts all available surface-exposed residues of the HSK determinant. This broad epitope coverage facilitates cross-genotypic reactivity and recognition of common mutations reported in HCV quasispecies, albeit to a varying degree. Certain mutations did abrogate T cell reactivity; however, natural variants comprising these mutations are reportedly rare and transient in nature, presumably due to fitness costs. Overall, despite a narrow bias, the TCR accommodated frequent mutations by acting like a blanket over the hypervariable epitope, thereby providing effective viral immunity. Our findings simultaneously advance the understanding of anti-HCV immunity and indicate the potential for cross-genotype HCV vaccines.

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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.…”

mentioning

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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Antigen-Driven Patterns of TCR Bias Are Shared across Diverse Outcomes of Human Hepatitis C Virus Infection

Cited by 25 publications

References 32 publications

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

An Extensive Antigenic Footprint Underpins Immunodominant TCR Adaptability against a Hypervariable Viral Determinant

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

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