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Infant and Adult Human B Cell Responses to Rotavirus Share Common Immunodominant Variable Gene Repertoires ¹

Jörn-Hendrik Weitkamp^*, Nicole Kallewaard, Koichi Kusuhara^2,*, Elizabeth Bures^*, John V. Williams^*, Bonnie LaFleur, Harry B. Greenberg and James E. Crowe, Jr.^3,*,

Departments of ^* Pediatrics, Microbiology and Immunology, and Preventive Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305

Ab repertoires exhibit marked restrictions during fetal life characterized by biases of variable gene usage and lack of junctional diversity. We tested the hypothesis that Ab repertoire restriction contributes to the observed poor quality of specific Ab responses made by infants to viral infections. We analyzed the molecular determinants of B cell responses in humans to two Ags of rotavirus (RV), a common and clinically important infection of human infants. We sequenced Ab H and L chain V region genes (V_H and V_L) of clones expanded from single B cells responding to RV virus protein 6 or virus protein 7. We found that adults exhibited a distinct bias in use of gene segments in the V_H1 and V_H4 families, for example, V_H1–46, V_H4–31, and V_H4–61. This gene segment bias differed markedly from the V_H3 dominant bias seen in randomly selected adult B cells. Recombinant Abs incorporating any of those three immunodominant V_H segments bound to RV-infected cells and also to purified RV particles. The RV-specific B cell repertoires of infants aged 2–11 mo and those of adults were highly related when compared by V_H, D, J_H, V_L, and J_L segment selection, extent of junctional diversity, and mean H chain complementarity determining region 3 length. These data suggest that residual fetal bias of the B cell repertoire is not a limiting determinant of the quality of Ab responses to viruses of infants beyond the neonatal period.

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