Epitope prediction and identification- adaptive T cell responses in humans

Sidney, John; Peters, Bjoern; Sette, Alessandro

doi:10.1016/j.smim.2020.101418

Cited by 45 publications

(45 citation statements)

References 166 publications

(194 reference statements)

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“…The most striking example observed here is the 29-member TRBV19+/TRBJ2-7+ cluster recognizing the well-documented immunodominant HLA-A*02:01-restricted GILGFVFTL peptide. The factors contributing to the activation of such a large T cell family within an individual also likely underlie immunodominance across individualsnamely, a high generation probability of T cell precursors capable of recognizing the antigen, and abundant or sustained expression of the antigen during infection 4,24 (Sidney et al, 2020;Oseroff et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…The identification, within complex repertoires, of T cells specific for a target of interest is an essential immunological capability, used to diagnose infection 1 (Nyendak et al, 2009) and measure the immunogenicity of vaccines and immunotherapies 2 (Flaxman and Ewer, 2018). Current methods for quantifying rare antigen-specific T cells include assays that measure antigen-stimulated cytokine production (e.g., immunospot assays and flow cytometric detection of intracellular cytokines 3,4 (Lovelace and Maecker, 2011; Sidney et al, 2020)), as well as assays that use labeled peptide:MHC probes to directly detect antigen-binding T cells 5 (Altman et al, 1996). Although widely useful, the ability to multiplex these assays across targets is limited, as is their sensitivity to detect rare T cell responses.…”

Section: Introductionmentioning

confidence: 99%

“…T cells recognize MHC-restricted peptide antigens by means of the heterodimeric T Cell Receptor (TCR), encoded by somatically-diversified and β loci 6 (Davis et al, 1984). The rearranged TCR α :β sequence pair completely determines a T cell's specificity, and current technologies enable >10 7 unpaired or >10 4 paired TCR chains to be routinely sequenced from a sample 7 (Yost et al, 2020). In contrast to traditional methods of antigen-specific T cell detection, deep sequencing of TCRs can reveal complete repertoires with high sensitivity.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A framework to identify antigen-expanded T Cell Receptor (TCR) clusters within complex repertoires

Ceglia

Kelley

Boyle

et al. 2021

Preprint

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Common approaches for monitoring T cell responses are limited in their multiplexity and sensitivity. In contrast, deep sequencing of the T Cell Receptor (TCR) repertoire offers a global view whose theoretical sensitivity is limited only by the depth of available sampling. However, assignment of antigen specificities within TCR repertoires has become a bottleneck. Here, we combine antigen-driven expansion, deep TCR sequencing and a novel analysis framework to show that homologous "Clusters of Expanded TCRs (CETs)" can be confidently identified without cell isolation, and assigned to antigen against a background of non-specific clones. We show that clonotypes within each CET respond to the same epitope, and that protein antigens stimulate multiple CETs reactive to constituent peptides. Finally, we demonstrate the personalized assignment of antigen-specificity to rare clones within fully-diverse unexpanded repertoires. The method presented here may be used to monitor T cell responses to vaccination and immunotherapy with high fidelity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A framework to identify antigen-expanded T Cell Receptor (TCR) clusters within complex repertoires

Ceglia

Kelley

Boyle

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…The second feature of interest is the promiscuity of epitopes. Promiscuous epitopes that bind across different alleles are more suitable for discovery because they tend to be immunodominant epitopes towards which the bulk of the immune response is skewed [ 35 ]. Moreover, this prevents the confounding of immunological evaluation by HLA type restrictions.…”

Section: Methodsmentioning

confidence: 99%

HLA-DRB1 Alleles Associated with Lower Leishmaniasis Susceptibility Share Common Amino Acid Polymorphisms and Epitope Binding Repertoires

et al. 2021

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Susceptibility for leishmaniasis is largely dependent on host genetic and immune factors. Despite the previously described association of human leukocyte antigen (HLA) gene cluster variants as genetic susceptibility factors for leishmaniasis, little is known regarding the mechanisms that underpin these associations. To better understand this underlying functionality, we first collected all known leishmaniasis-associated HLA variants in a thorough literature review. Next, we aligned and compared the protection- and risk-associated HLA-DRB1 allele sequences. This identified several amino acid polymorphisms that distinguish protection- from risk-associated HLA-DRB1 alleles. Subsequently, T cell epitope binding predictions were carried out across these alleles to map the impact of these polymorphisms on the epitope binding repertoires. For these predictions, we used epitopes derived from entire proteomes of multiple Leishmania species. Epitopes binding to protection-associated HLA-DRB1 alleles shared common binding core motifs, mapping to the identified HLA-DRB1 amino acid polymorphisms. These results strongly suggest that HLA polymorphism, resulting in differential antigen presentation, affects the association between HLA and leishmaniasis disease development. Finally, we established a valuable open-access resource of putative epitopes. A set of 14 HLA-unrestricted strong-binding epitopes, conserved across species, was prioritized for further epitope discovery in the search for novel subunit-based vaccines.

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“…The second feature of interest is the promiscuity of epitopes. Promiscuous epitopes that bind across different alleles are more suitable for discovery because they tend to be immunodominant epitopes towards which the bulk of the immune response is skewed [35]. Moreover, this prevents confounding of immunological evaluation by HLA type restrictions.…”

Section: Methodsmentioning

confidence: 99%

Predicted epitope binding core motifs and common amino acid polymorphisms distinguish protective- from susceptibility-associated HLA alleles in leishmaniasis

Vrij

Meysman

Gielis

et al. 2021

Preprint

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Susceptibility for leishmaniasis is largely dependent on genetic- and immune factors of the host. Despite the previously described association of human leukocyte antigen (HLA) gene cluster variants as genetic susceptibility factors, little is known on the mechanisms that mediate these associations. To characterize the functionality underpinning these associations between HLA and disease, we predicted the epitope binding repertoires for all known leishmaniasis-associated HLA variants collected in a thorough literature review. We identified several amino acid polymorphisms in the HLA sequences that distinguished protective- from risk-associated HLA-DRB1 alleles. Proteome-wide and multi-species T cell epitope binding pre-dictions were carried out across these alleles, enabling us to map the effects on the epitope binding repertoires. The protective-associated HLA-DRB1 alleles were characterized by common binding core motifs, which map to the identified amino acid polymorphisms. These results strongly suggest that polymorphism in the HLA region, resulting in differential anti-gen presentation, affects the association between HLA and leishmaniasis disease development. Finally, we established a valuable open-access resource of putative epitopes, of which a set of 14 HLA-unrestricted strong-binding epitopes, conserved across species, were prioritized for further epitope discovery in the search for novel subunit-based vaccines.

show abstract

Epitope prediction and identification- adaptive T cell responses in humans

Cited by 45 publications

References 166 publications

A framework to identify antigen-expanded T Cell Receptor (TCR) clusters within complex repertoires

A framework to identify antigen-expanded T Cell Receptor (TCR) clusters within complex repertoires

HLA-DRB1 Alleles Associated with Lower Leishmaniasis Susceptibility Share Common Amino Acid Polymorphisms and Epitope Binding Repertoires

Predicted epitope binding core motifs and common amino acid polymorphisms distinguish protective- from susceptibility-associated HLA alleles in leishmaniasis

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