TCR-ligand dissociation rate is a robust and stable biomarker of CD8+ T cell potency

Allard, Mathilde; Couturaud, Barbara; Carretero-Iglesia, Laura; Duong, Minh Ngoc; Schmidt, Julien; Monnot, Gwennaëlle; Romero, Pedro; Speiser, Daniel E.; Hebeisen, Michael; Rufer, Nathalie

doi:10.1172/jci.insight.92570

Cited by 38 publications

(58 citation statements)

References 70 publications

(152 reference statements)

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“…FA changes in vitro depended on the timing postactivation, and the antigen concentration used, which both impact the activation-dependent changes in receptor levels involved in the immune synapse, and consequently the FA. Similar activation state-dependent FA changes can also be observed in human CD8 T-cell clones analyzed in vitro [28]. These results also point to an important methodological aspect: in order to obtain reproducible FA data, T-cell clones must always be analyzed after the same number of days since their last restimulation.…”

Section: Discussionsupporting

confidence: 65%

“…Supporting Information Fig. 3 shows these previously published data [28] in more detail, where peptide-specific CD8 T-cell clones were cultured from the PBMC of vaccinated melanoma patients. These results emphasize that human CD8 Tcell clones consistently increase their FA from day 10 to day 15 after restimulation, in parallel to the steady reduction of their activation state [28].…”

Section: Fa Improves In Vitro With Increased Time After Activationmentioning

confidence: 98%

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Murine CD8 T‐cell functional avidity is stable in vivo but not in vitro: Independence from homologous prime/boost time interval and antigen density

et al. 2019

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It is known that for achieving high affinity antibody responses, vaccines must be optimized for antigen dose/density, and the prime/boost interval should be at least 4 weeks. Similar knowledge is lacking for generating high avidity T‐cell responses. The functional avidity (FA) of T cells, describing responsiveness to peptide, is associated with the quality of effector function and the protective capacity in vivo. Despite its importance, the FA is rarely determined in T‐cell vaccination studies. We addressed the question whether different time intervals for short‐term homologous vaccinations impact the FA of CD8 T‐cell responses. Four‐week instead of 2‐week intervals between priming and boosting with potent subunit vaccines in C57BL/6 mice did not improve FA. Equally, similar FA was observed after vaccination with virus‐like particles displaying low versus high antigen densities. Interestingly, FA was stable in vivo but not in vitro, depending on the antigen dose and the time interval since T‐cell activation, as observed in murine monoclonal T cells. Our findings suggest dynamic in vivo modulation for equal FA. We conclude that low antigen density vaccines or a minimal 4‐week prime/boost interval are not crucial for the T‐cell's FA, in contrast to antibody responses.

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Section: Discussionsupporting

confidence: 65%

Section: Fa Improves In Vitro With Increased Time After Activationmentioning

confidence: 98%

Murine CD8 T‐cell functional avidity is stable in vivo but not in vitro: Independence from homologous prime/boost time interval and antigen density

et al. 2019

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“…TCR-ligand dissociation rate stands out as a robust biomarker to directly evaluate and quantify the potency of an immunotherapy intervention (e.g., the type of peptide used for vaccination) in melanoma patients (33,34). To explore the impact of TCR/CD8binding avidity for pMHC on different vaccine-induced T-cell responses according to peptide and CpG doses, we generated large representative libraries of Melan-A-specific CD8 T-cell clones (n = 454) derived from effector-memory CD28 pos (early-differentiated EM28 pos ) or CD28 neg (late-differentiated EM28 neg ) cells by direct ex vivo sorting and cloning from seven melanoma patients ( Figure 1E, Supplementary Figure 3).…”

Section: High Peptide Dose Favors the Early Selection Of Vaccine-indumentioning

confidence: 99%

“…Consequently, there is a large body of evidence revealing that enhanced TCR-pMHC binding avidity correlates with augmented T-cell functionality (26)(27)(28)(29)(30) as well as in vivo improved tumor growth control in cancer patients (31,32). Using fluorescent reversible NTAmers, we recently showed that the TCR-pMHC binding avidity accurately predicted T-cell functional potency of anti-cancer and virus-specific CD8 T-cell responses (33). Moreover, we performed a complete characterization of TCR-pMHC avidity of tumorspecific CD8 T-cells induced by peptide-based vaccination of melanoma patients and found differences in TCR-pMHC binding avidity depending on the type of Melan-A MART−1 26−35 peptide used for vaccination.…”

Section: Introductionmentioning

confidence: 99%

High Peptide Dose Vaccination Promotes the Early Selection of Tumor Antigen-Specific CD8 T-Cells of Enhanced Functional Competence

et al. 2020

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CD8 T-cell response efficiency critically depends on the TCR binding strength to peptide-MHC, i.e., the TCR binding avidity. A current challenge in onco-immunology lies in the evaluation of vaccine protocols selecting for tumor-specific T-cells of highest avidity, offering maximal immune protection against tumor cells and clinical benefit. Here, we investigated the impact of peptide and CpG/adjuvant doses on the quality of vaccine-induced CD8 T-cells in relation to binding avidity and functional responses in treated melanoma patients. Using TCR-pMHC binding avidity measurements combined to phenotype and functional assays, we performed a comprehensive study on representative tumor antigen-specific CD8 T-cell clones (n = 454) from seven patients vaccinated with different doses of Melan-A/ELA peptide (0.1 mg vs. 0.5 mg) and CpG-B adjuvant (1-1.3 mg vs. 2.6 mg). Vaccination with high peptide dose favored the early and strong in vivo expansion and differentiation of Melan-A-specific CD8 T-cells. Consistently, T-cell clones generated from those patients showed increased TCR binding avidity (i.e., slow off-rates and CD8 binding independency) readily after 4 monthly vaccine injections (4v). In contrast, the use of low peptide or high CpG-B doses required 8 monthly vaccine injections (8v) for the enrichment of anti-tumor T-cells with high TCR binding avidity and low CD8 binding dependency. Importantly, the CD8 binding-independent vaccineinduced CD8 T-cells displayed enhanced functional avidity, reaching a plateau of maximal function. Thus, T-cell functional potency following peptide/CpG/IFA vaccination may not be further improved beyond a certain TCR binding avidity limit. Our results also indicate that while high peptide dose vaccination induced the early selection of Melan-A-specific CD8 T-cells of increased functional competence, continued serial vaccinations also promoted such high-avidity T-cells. Overall, the systematic assessment of T-cell binding avidity may contribute to optimize vaccine design for improving clinical efficacy.

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“…Using reversible MHC multimers, such as MHC streptamers, it is possible to precisely determine the k off ‐rate of surface‐bound pMHC monomers and thereby calculate the half‐life of TCR‐pMHC/CD8 interactions . k off ‐rate assays do not take into account the k on ‐rate and thereby do not measure TCR avidity per se, but the k off ‐rate has been shown to be predictive of both structural avidity and in vivo functionality, although this correlation may not necessarily be completely linear. Early work hinted at an optimal dwell‐time of interactions between TCRs and pMHC complexes, and also most of experimental data that accumulated over the years thereafter supported a kinetic proofreading model of T‐cell activation with limited signaling, which suggested an optimal dissociation time for maximum T‐cell activation .…”

Section: Generation Of Naive Tcr Repertoiresmentioning

confidence: 99%

TCR repertoire evolution during maintenance of CMV‐specific T‐cell populations

Schober

Buchholz

Busch

2018

Immunological Reviews

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During infections and cancer, the composition of the T-cell receptor (TCR) repertoire of antigen-specific CD8 T cells changes over time. TCR avidity is thought to be a major driver of this process, thereby interacting with several additional regulators of T-cell responses to form a composite immune response architecture. Infections with latent viruses, such as cytomegalovirus (CMV), can lead to large T-cell responses characterized by an oligoclonal TCR repertoire. Here, we review the current status of experimental studies and theoretical models of TCR repertoire evolution during CMV infection. We will particularly discuss the degree to which this process may be determined through structural TCR avidity. As engineered TCR-redirected T cells have moved into the spotlight for providing more effective immunotherapies, it is essential to understand how the key features of a given TCR influence T-cell expansion and maintenance in settings of infection or malignancy. Deeper insights into these mechanisms will improve our basic understanding of T-cell immunology and help to identify optimal TCRs for immunotherapy.

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TCR-ligand dissociation rate is a robust and stable biomarker of CD8+ T cell potency

Cited by 38 publications

References 70 publications

Murine CD8 T‐cell functional avidity is stable in vivo but not in vitro: Independence from homologous prime/boost time interval and antigen density

Murine CD8 T‐cell functional avidity is stable in vivo but not in vitro: Independence from homologous prime/boost time interval and antigen density

High Peptide Dose Vaccination Promotes the Early Selection of Tumor Antigen-Specific CD8 T-Cells of Enhanced Functional Competence

TCR repertoire evolution during maintenance of CMV‐specific T‐cell populations

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