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Secondary immunisation with high‐dose heterologous peptide leads to CD8 T cell populations with reduced functional avidity

Expansion of high‐ or low‐avidity CD8 T cells in vitro inversely correlates with the concentration of peptide ligand present during culture. In contrast, the selective enrichment of high‐ or low‐avidity T cell populations in vivo using peptide immunisation is not well documented. In our study, a single immunisation with different doses of wild‐type peptide or a variant peptide able to stimulate CTL responses cross‐reactive with wild‐type peptide failed to shift the average avidity of the responding CD8 T cell population specific to either peptide. However, in contrast to homologous prime‐boost immunisation, heterologous prime‐boost immunisation incorporating high doses of the second immunogen resulted in peptide‐specific CD8 T cell populations polarized toward a low average functional avidity. These data suggest that sequential exposure to structurally related viral peptides could impair rather than promote anti‐viral immunity by lowering the avidity of the responding CD8 T cell population. This study has implications for improving vaccine strategies against viruses and tumours and enhances our understanding of heterologous immunity during sequential viral infection.