Selection of T Cell Clones Expressing High-Affinity Public TCRs within Human Cytomegalovirus-Specific CD8 T Cell Responses

Assessment of clonal diversity of T cell responses against human CMV (HCMV), a major cause of morbidity in immunodepressed patients, provides important insights into the molecular basis of T cell immunodominance, and has also clinical implications for the immunomonitoring and immunotherapy of HCMV i...

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Bibliographic Details
Published in:Journal of Immunology 2005-11, Vol.175 (9), p.6123-6132
Main Authors: Trautmann, Lydie, Rimbert, Marie, Echasserieau, Klara, Saulquin, Xavier, Neveu, Berangere, Dechanet, Julie, Cerundolo, Vincenzo, Bonneville, Marc
Format: Article
Language:English
Subjects:
Antibodies, Monoclonal - immunology
CD8 Antigens - physiology
CD8-Positive T-Lymphocytes - immunology
Cell Line
Cytomegalovirus - immunology
Human cytomegalovirus
Humans
Immunodominant Epitopes
Life Sciences
Other
Phosphoproteins - immunology
Receptors, Antigen, T-Cell, alpha-beta - chemistry
Receptors, Antigen, T-Cell, alpha-beta - metabolism
Viral Matrix Proteins - immunology
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Summary:Assessment of clonal diversity of T cell responses against human CMV (HCMV), a major cause of morbidity in immunodepressed patients, provides important insights into the molecular basis of T cell immunodominance, and has also clinical implications for the immunomonitoring and immunotherapy of HCMV infections. We performed an in-depth molecular and functional characterization of CD8 T cells directed against an immunodominant HLA-A2-restricted epitope derived from HCMV protein pp65 (NLV/A2) in steady state and pathological situations associated with HCMV reactivation. NLV/A2-specific T cells in healthy HCMV-seropositive donors showed limited clonal diversity and usage of a restricted set of TCR Vbeta regions. Although TCRbeta-chain junctional sequences were highly diverse, a large fraction of NLV/A2-specific T cells derived from distinct individuals showed several recurrent (so-called "public") TCR features associated in some cases with full conservation of the TCRalpha chain junctional region. A dramatic clonal focusing of NLV/A2-specific T cells was observed in situations of HCMV reactivation and/or chronic inflammation, which resulted in selection of a single clonotype displaying similar public TCR features in several patients. In most instances the NLV/A2-specific dominant clonotypes showed higher affinity for their Ag than subdominant ones, thus suggesting that TCR affinity/avidity is the primary driving force underlying repertoire focusing along chronic antigenic stimulation.
ISSN:0022-1767
1550-6606
1365-2567
DOI:10.4049/jimmunol.175.9.6123