Immunodominance of major histocompatibility complex class I-restricted influenza virus epitopes can be influenced by the T-cell receptor repertoire

Abstract

We have used T-cell receptor beta-chain transgenic mice to determine the effects of a limited T-cell receptor repertoire on major histocompatibility complex class I-restricted epitope selection during the course of an influenza virus infection. Analysis of T-cell hybridomas generated from wild-type and transgenic mice demonstrated that the viral epitope recognized depended on the available T-cell receptor repertoire. Wild-type T-cell hybridomas recognized epitopes derived from the nucleoprotein and basic polymerase molecules, whereas hybridomas generated from transgenic mice recognized epitopes derived from the nonstructural protein and the matrix protein. There was no overlap in specificity between the two panels of hybridomas. This reciprocal pattern of specificity was also apparent in cytoxicity assays with brochoalveolar lavage cells isolated from the lungs of influenza virus-infected mice. T-cell receptor usage in the transgenic hybridomas was very restricted, with only one V alpha element used for ech of the two viral epitopes recognized. In the case of the hybridomas reactive to the nonstructural protein, sequence analysis showed that they all expressed V alpha 4J alpha 32 chains associated with the same junctional amino acids (Leu-Leu) that were encoded by five different nucleotide sequences, indicating a strong selection for T-cell receptor usage. Taken together, these data demonstrate that the available T-cell receptor repertoire can have a profound effect on the immunodominance of class I-restricted epitopes during a viral infection.