title: CD8+ TCR repertoire formation is guided primarily by the peptide component of the antigenic complex.
abstract: CD8(+) T cells recognize infected or dysregulated cells via the clonotypically expressed αβ TCR, which engages Ag in the form of peptide bound to MHC class I (MHC I) on the target cell surface. Previous studies have indicated that a diverse Ag-specific TCR repertoire can be beneficial to the host, yet the determinants of clonotypic diversity are poorly defined. To better understand the factors that govern TCR repertoire formation, we conducted a comprehensive clonotypic analysis of CD8(+) T cell populations directed against epitopes derived from EBV and CMV. Neither pathogen source nor the restricting MHC I molecule were linked with TCR diversity; indeed, both HLA-A and HLA-B molecules were observed to interact with an overlapping repertoire of expressed TRBV genes. Peptide specificity, however, markedly impacted TCR diversity. In addition, distinct peptides sharing HLA restriction and viral origin mobilized TCR repertoires with distinct patterns of TRBV gene usage. Notably, no relationship was observed between immunodominance and TCR diversity. These findings provide new insights into the forces that shape the Ag-specific TCR repertoire in vivo and highlight a determinative role for the peptide component of the peptide-MHC I complex on the molecular frontline of CD8(+) T cell-mediated immune surveillance.
authors.affiliation: Department of Immunology, University Medical Center Utrecht, Utrecht 3584 EA, The Netherlands.
authors.forename: Dan
authors.initials: D
authors.lastname: Koning
authors.forename: Ana I
authors.initials: AI
authors.lastname: Costa
authors.forename: Ilka
authors.initials: I
authors.lastname: Hoof
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: Nening M
authors.initials: NM
authors.lastname: Nanlohy
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthews
authors.forename: Vanessa
authors.initials: V
authors.lastname: Venturi
authors.forename: Ingrid M M
authors.initials: IM
authors.lastname: Schellens
authors.forename: Jose A M
authors.initials: JA
authors.lastname: Borghans
authors.forename: Can
authors.initials: C
authors.lastname: Kesmir
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Debbie
authors.initials: D
authors.lastname: van Baarle
mesh_terms: D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D060966:Clonal Selection, Antigen-Mediated; D003587:Cytomegalovirus / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D015329:Gene Rearrangement, T-Lymphocyte / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology*; D015235:HLA-B Antigens / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D007157:Immunologic Surveillance; D007371:Interferon-gamma / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D000939:Epitopes; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D007371:Interferon-gamma