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Departments of
*
Neurology and
Molecular Microbiology and Immunology, University of Southern California School of Medicine, Los Angeles, CA 90033;
Immunobiology Center, Northwestern University Medical School, Chicago, IL 60601; and
§
Department of Molecular Biotechnology and Immunology, University of Washington, Seattle, WA 981195
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 
/ß-chain
heterogeneity. Direct ex vivo analysis of CNS-derived mononuclear cells
by IFN-
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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