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Repertoire Shift in the Humoral Response to Phosphocholine-Keyhole Limpet Hemocyanin: V_H Somatic Mutation in Germinal Center B Cells Impairs T15 Ig Function¹

Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239

Phosphocholine (PC) is a naturally occurring Ag common to many pathogenic microorganisms. Early in the primary response to PC conjugated to keyhole limpet hemocyanin (KLH), T15 Id⁺ Abs constitute >90% of the serum Ig in BALB/c mice. During the late primary and memory response to PC-protein, a shift in the repertoire occurs and T15 Id⁺ Abs lose dominance. In this study, we use immunohistochemistry and single germinal center microdissection to locate T15 Id⁺ cells in the spleen in a primary response to PC-KLH. We demonstrate T15 Id⁺ B cells and V_H1-DFL16.1-JH1 and V22-J5 rearrangements in germinal centers early in the immune response; thus loss of T15 dominance is not due to lack of T15 cells within germinal centers. One-hundred thirty one V_H1 and 57 V22 rearrangements were cloned and sequenced. Thirty four percent of the V_H1 clones and 37% of the V22 clones contained somatic mutations indicating participation in the germinal center response. Six variant T15 H clones were expressed with wild-type T15 L chain in vitro. Two of these Abs were defective in secretion providing the first evidence that mutation occurring in vivo can disrupt Ig assembly and secretion. Of the four secretion-competent Abs, two failed to display binding to PC-protein, while the other two displayed altered carrier recognition. These results indicate that somatic mutation of T15 in vivo can result in the loss of binding and secretion, potentially leading to B cell wastage. The failure of T15 to gain affinity enhancing mutations in the face of these detrimental changes may contribute to repertoire shift.

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