Back to Search Start Over

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

Authors :
Mikhail V. Pogorelyy
Alla D. Fedorova
James E. McLaren
Kristin Ladell
Dmitri V. Bagaev
Alexey V. Eliseev
Artem I. Mikelov
Anna E. Koneva
Ivan V. Zvyagin
David A. Price
Dmitry M. Chudakov
Mikhail Shugay
Source :
Genome Medicine, Vol 10, Iss 1, Pp 1-14 (2018)
Publication Year :
2018
Publisher :
BMC, 2018.

Abstract

Abstract 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.

Details

Language :
English
ISSN :
1756994X
Volume :
10
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Genome Medicine
Publication Type :
Academic Journal
Accession number :
edsdoj.845a169f8e4440afa7d30ed71f7b4f65
Document Type :
article
Full Text :
https://doi.org/10.1186/s13073-018-0577-7