Exploring the pre-immune landscape of antigen-specific T cells

Background Adaptive immune responses to newly encountered pathogens depend on the mobilization of antigen-specific clonotypes from a vastly diverse pool of naive T cells. Using recent advances in immune repertoire sequencing technologies, models of the immune receptor rearrangement process, and a da...

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Veröffentlicht in:Genome medicine Jg. 10; H. 1; S. 68 - 14
Hauptverfasser: Pogorelyy, Mikhail V., Fedorova, Alla D., McLaren, James E., Ladell, Kristin, Bagaev, Dmitri V., Eliseev, Alexey V., Mikelov, Artem I., Koneva, Anna E., Zvyagin, Ivan V., Price, David A., Chudakov, Dmitry M., Shugay, Mikhail
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London BioMed Central 25.08.2018
BioMed Central Ltd
Springer Nature B.V
BMC
Schlagworte:
Adaptive immunity
Ankylosing spondylitis
Antigen
Antigens
Bioinformatics
Biomedical and Life Sciences
Biomedicine
Cancer Research
Care and treatment
Computer applications
Cord blood
Cytomegalovirus
Epitopes
Epitopes - immunology
Estimates
Genetic aspects
Genomics of Infection and Immunity
Histocompatibility antigen HLA
Histocompatibility Antigens Class I - immunology
Human Genetics
Humans
Immune repertoire
Immune system
Immunogenicity
Lymphocytes
Lymphocytes T
Medicine/Public Health
Metabolomics
Models, Statistical
Multiculturalism & pluralism
Pathogens
Peptides - immunology
Physicochemical properties
Receptors, Antigen, T-Cell - immunology
Systems Biology
T cell receptor
T cell receptors
T cells
T-Lymphocytes - immunology
Umbilical cord
Antigen
T cell receptor
Immunogenicity
Immune repertoire
ISSN:1756-994X, 1756-994X
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Zusammenfassung:Background Adaptive immune responses to newly encountered pathogens depend on the mobilization of antigen-specific clonotypes from a vastly diverse pool of naive T cells. Using recent advances in immune repertoire sequencing technologies, models of the immune receptor rearrangement process, and a database of annotated T cell receptor (TCR) sequences with known specificities, we explored the baseline frequencies of T cells specific for defined human leukocyte antigen (HLA) class I-restricted epitopes in healthy individuals. Methods We used a database of TCR sequences with known antigen specificities and a probabilistic TCR rearrangement model to estimate the baseline frequencies of TCRs specific to distinct antigens epitopespecificT-cells. We verified our estimates using a publicly available collection of TCR repertoires from healthy individuals. We also interrogated a database of immunogenic and non-immunogenic peptides is used to link baseline T-cell frequencies with epitope immunogenicity. Results Our findings revealed a high degree of variability in the prevalence of T cells specific for different antigens that could be explained by the physicochemical properties of the corresponding HLA class I-bound peptides. The occurrence of certain rearrangements was influenced by ancestry and HLA class I restriction, and umbilical cord blood samples contained higher frequencies of common pathogen-specific TCRs. We also identified a quantitative link between specific T cell frequencies and the immunogenicity of cognate epitopes presented by defined HLA class I molecules. Conclusions Our results suggest that the population frequencies of specific T cells are strikingly non-uniform across epitopes that are known to elicit immune responses. This inference leads to a new definition of epitope immunogenicity based on specific TCR frequencies, which can be estimated with a high degree of accuracy in silico, thereby providing a novel framework to integrate computational and experimental genomics with basic and translational research efforts in the field of T cell immunology.
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ISSN:1756-994X
1756-994X
DOI:10.1186/s13073-018-0577-7