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*
Vaccine and Gene Therapy Institute, Oregon Health Sciences University, Portland, OR 97201;
Graduate Program in Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
Institut für Medizinische Immunologie, Berlin, Germany; and
Becton Dickinson Biosciences, San Jose, CA 95131
High steady-state frequencies of CMV-specific CD4+
memory T cells are maintained in CMV-exposed subjects, and these cells
are thought to play a key role in the immunologic control of this
permanent infection. However, the essential components of this response
are poorly defined. Here, we report the use of a step-wise application
of flow cytometric and molecular techniques to determine the number and
size of the TCR V
-defined clonotypes within freshly obtained
CMV-specific CD4+ memory T cell populations of four
healthy, CMV-exposed human subjects. This analysis revealed a stable
clonotypic hierarchy in which 1–3 dominant clonotypes are maintained
in concert with more numerous subdominant and minor clonotypes. These
dominant clonotypes accounted for 10–50% of the overall CMV response,
and comprised from 0.3 to 4.0% of peripheral blood CD4+ T
cells. Two subjects displayed immunodominant responses to single
epitopes within the CMV matrix phosphoprotein pp65; these single
epitope responses were mediated by a single dominant clonotype in one
subject, and by multiple subdominant and minor clonotypes in the other.
Thus, the CMV-specific CD4+ T cell memory repertoire in
normal subjects is characterized by striking clonotypic dominance and
the potential for epitope focusing, suggesting that primary
responsibility for immunosurveillance against CMV reactivation rests
with a handful of clones recognizing a limited array of CMV
determinants. These data have important implications for the
understanding of mechanisms by which a genetically stable chronic viral
pathogen such as CMV is controlled, and offer possible insight into the
failure of such control for a genetically flexible pathogen like
HIV-1.
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