The polyclonal CD8 T cell response to influenza M158-66 generates a fully connected network of cross-reactive clonotypes to structurally related peptides: a paradigm for memory repertoire coverage of novel epitopes or escape mutants. J Immunol 2011 Jun 01;186(11):6390-7
Date
04/27/2011Pubmed ID
21518969Pubmed Central ID
PMC4513670DOI
10.4049/jimmunol.1004031Scopus ID
2-s2.0-79958020932 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
Cross-reactivity of T cells is defined as recognition of two or more peptide-MHC complexes by the same T cell. Although examples of cross-reactivity have been reported, a detailed examination of cross-reactivity has not been performed. In this study, we took advantage of the high degree of polyclonality in the BV19 T cell repertoire responding to influenza M1(58-66) in HLA-A2 individuals to obtain a measure of simple cross-reactivity. We used substitutions that incrementally change the structure of the M1(58-66) peptide to measure how the HLA-A2-restricted response adapts to these changes. In three HLA-A2 adult subjects, we identified the BV19 clonotypes in the recall response to the influenza epitope M1(58-66) and 12 M1 peptides substituted at TCR contact position 63 or 65. The fraction of cross-reactive clonotypes in the M1(58-66) repertoire varied from 45-58% in the three donors. The extent of cross-reactivity, which is the additional number of peptides recognized by a single clonotype, is as high as six. We summarized the data using graph theory, with the cross-reactive clonotypes connecting the different HLA-A2 peptides recognized. The cross-reactive clonotypes form a well-connected network that could provide protection from virus-escape variants. We predict that any new pathogen with an epitope whose shape corresponds to that of the peptides that we studied would find a pre-existing repertoire ready to respond to it. We propose that in adult memory repertoires, previously encountered epitopes may have generated similar cross-reactive repertoires.
Author List
Petrova GV, Naumova EN, Gorski JMESH terms used to index this publication - Major topics in bold
AdultAmino Acid Sequence
Amino Acid Substitution
Antigens, Viral
Base Sequence
CD8-Positive T-Lymphocytes
Cells, Cultured
Clone Cells
Cross Reactions
Cytotoxicity, Immunologic
Epitopes, T-Lymphocyte
HLA-A2 Antigen
Humans
Immune Evasion
Immunologic Memory
Influenza A virus
Middle Aged
Models, Immunological
Mutation
Peptides
Receptors, Antigen, T-Cell
T-Lymphocytes, Cytotoxic
Viral Matrix Proteins