T Cell Receptor Clonotype Influences Epitope Hierarchy in the CD8+T Cell Response to Respiratory Syncytial Virus Infection

CD8+ T cell responses are important for recognizing and resolving viral infections. To better understand the selection and hierarchy of virus-specific T cell responses, we compared the T cell receptor (TCR) clonotype in parent and hybrid strains of respiratory syncytial virus-infected mice. K(d)M2(82-90) (SYIGSINNI) in BALB/c and (DM187-195)-M-b (NAITNAKII) in C57B1/6 are both dominant epitopes in parent strains but assume a distinct hierarchy, with K(d)M2(82-90) dominant to (DM187-195)-M-b in hybrid CB6F1/J mice. The dominant K(d)M2(82-90) response is relatively public and is restricted primarily to the highly prevalent V beta 13.2 in BALB/c and hybrid mice, whereas (DM187-195)-M-b responses in C57BL/6 mice are relatively private and involve multiple V beta subtypes, some of which are lost in hybrids. A significant frequency of TCR CDR3 sequences in the (DM187-195)-M-b response have a distinct "(D/E) WG" motif formed by a limited number of recombination strategies. Modeling of the dominant epitope suggested a flat, featureless structure, but (DM187-195)-M-b showed a distinctive structure formed by Lys(7). The data suggest that common recombination events in prevalent V beta genes may provide a numerical advantage in the T cell response and that distinct epitope structures may impose more limited options for successful TCR selection. Defining how epitope structure is interpreted to inform T cell function will improve the design of future gene-based vaccines.