Profile of a Serial Killer: Cellular and Molecular Approaches to Study Individual Cytotoxic T-Cells following Therapeutic Vaccination
Figure 3
TCR repertoire restriction and TCR clonotype selection are driven by differentiation. Analysis of TCR repertoire diversity and clonotype composition between tumor-specific responses (left side of the figure) and viral-specific responses (right side of the figure) suggest that all antigen-specific T-cell responses undergo selection along with progressive cellular differentiation (top to bottom of figure). As such, early differentiated subsets show a higher degree of clonal diversity relative to their more differentiated subsets. Nevertheless, dominant clonotypes are also found in the former but make up significantly larger proportions of the more differentiated compartments (defined as TCR clonotype selection) supporting a linear model of differentiation. In addition, viral-specific responses which are composed of highly differentiated cells (EMRA T-cells) also show a higher degree of TCR repertoire restriction compared with tumor-specific responses, evident not only in the late but also already in the early differentiated subsets (indicated by a decrease in numbers of BV families and numbers of clonotypes from left to right). Each colored slice of pie represents a unique TCR clonotype, while the grey slices represent nondominant TCRs, that is, the sequences identified only once within the antigen-specific TCR repertoire. Melan-A (ELAGIGILTV) and NY-ESO-1 (SLLMWITQC) peptide sequences are indicated for the tumor-specific responses; virus specific T-cells were analyzed for the epitope EBV BMLF1280–288 (GLCTLVAML) and for the CMV epitope pp65495–503 (NLVPMVATV). All responses are HLA-A2 restricted. Preferential TRBV family usage is depicted based on IMGT’s nomenclature [112].
