Key result
CD8+ T cells from persistently infected mice exhibited highly focused specificity for the wild-type sequence compared to broadly reactive CTLs from acutely infected mice.
Why the study?
Does viral persistence in the CNS influence the antigen specificity and TCR diversity of CD8+ T cells in mice?
Does viral persistence in the CNS influence the antigen specificity and TCR diversity of CD8+ T cells in mice?
Viral persistence in the CNS drives selective pressure resulting in the predominance of CD8+ T cells with highly focused antigen specificity.
Supports selective pressure from CNS persistence on T cell repertoire; leaves open human translation and therapeutic implications.
The relationships between T cell populations during primary viral infection and persistence are poorly understood. Mice infected with the neurotropic JHMV strain of mouse hepatitis virus mount potent regional CTL responses that effectively reduce infectious virus; nevertheless, viral RNA persists in the central nervous system (CNS). To evaluate whether persistence influences Ag-specific CD8+ T cells, functional TCR diversity was studied in spleen and CNS-derived CTL populations based on differential recognition of variant peptides for the dominant nucleocapsid epitope. Increased specificity of peripheral CTL from persistently infected mice for the index epitope compared with immunized mice suggested T cell selection during persistence. This was confirmed with CD8+ T cell clones derived from the CNS of either acutely (CTLac) or persistently (CTLper) infected mice. Whereas CTLac clones recognized a broad diversity of amino acid substitutions, CTLper clones exhibited exquisite specificity for the wild-type sequence. Highly focused specificity was CD8 independent but correlated with longer complementarity-determining regions 3 characteristic of CTLper clonotypes despite limited TCR alpha/beta-chain heterogeneity. Direct ex vivo analysis of CNS-derived mononuclear cells by IFN-gamma enzyme-linked immunospot assay confirmed the selection of T cells with narrow Ag specificity during persistence at the population level. These data suggest that broadly reactive CTL during primary infection are capable of controlling potentially emerging mutations. By contrast, the predominance of CD8+ T cells with dramatically focused specificity during persistence at the site of infection and in the periphery supports selective pressure driven by persisting Ag.
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Marten et al. (1999) studied Viral persistence in the central nervous system. Persistent viral infection vs. Acute infection or immunization was evaluated on Functional TCR diversity and specificity of CD8+ T cells. CD8+ T cells from persistently infected mice exhibited highly focused specificity for the wild-type sequence compared to broadly reactive CTLs from acutely infected mice.
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