The authors suspected that activation of cross-reactive memory T cells might be implicated in generating a restricted T-cell response and they used a mouse model of virus infection to investigate this further. They first showed that epitopes from lymphocytic choriomeningitis virus (LCMV NP205–212) and Pichinde virus (PV NP205–212) are cross-reactive: NP205-specific CD8+ T cells that are activated by primary infection with LCMV or PV produced IFN-γ in response to the heterologous NP205 peptide. Sequence analysis of the Vβ portion of the TCR (a region of the TCR that varies among T cells) showed that NP205-specific CD8+ T cells activated during acute LCMV or PV infection have a broad and diverse TCR repertoire. TCRs from NP205-specific CD8+ T cells obtained from LCMV-infected mice revealed hundreds of different TCR Vβ sequences or clonotypes. Once acute infection with LCMV or PV resolves, a pool of memory CD8+ T cells is established, including the cross-reactive NP205-specific CD8+ T cells. The authors went on to show that these cross-reactive T cells can have a profound influence on the memory T-cell repertoire. In PV-immune mice that are infected with LCMV, proliferation of cross-reactive PV NP205-specific memory CD8+ T cells results in a dominant NP205 response. But in contrast to the diverse CD8+ T-cell population induced by NP205 in acute infection, the TCR repertoire of NP205-specific CD8+ T cells after heterologous LCMV challenge is limited and dominated by specific Vβ clonotypes. These results indicate that only a small subset of the cross-reactive NP205-specific CD8+ T cells proliferate after heterologous infection. This oligoclonal TCR repertoire can favour the generation of viral escape mutants as shown by the isolation of an LCMV NP205-variant virus from PV-immune mice 8 months after LCMV challenge.
...it is the unique make-up ... of the crossreactive memory CD8+ T cells ... that determines the response to heterologous infection...
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