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 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.
Trautmann
Lydie
L
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 601, Nantes, France.
Rimbert
Marie
M
Echasserieau
Klara
K
Saulquin
Xavier
X
Neveu
Bérangère
B
Dechanet
Julie
J
Cerundolo
Vincenzo
V
Bonneville
Marc
M
D000911:Antibodies, Monoclonal / Q000276:immunology; D016827:CD8 Antigens / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D003587:Cytomegalovirus / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes; D010750:Phosphoproteins / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000276:immunology*
D000911:Antibodies, Monoclonal; D016827:CD8 Antigens; D016056:Immunodominant Epitopes; D010750:Phosphoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa