IgD shapes the pre-immune naive B cell compartment in humans

B cell maturation and immunoglobulin (Ig) repertoire selection are governed by expression of a functional B cell receptor (BCR). Naive B cells co-express their BCR as IgM and IgD isotype. However, the role of the additionally expressed IgD on naive B cells is not known. Here we assessed the impact of IgD on naive B cell maturation and Ig repertoire selection in 8 individuals from 3 different families with heterozygous loss-of-function or loss-of expression mutations in IGHD. Although naive B cells from these individuals expressed IgM on their surface, the IGHD variant in heterozygous state entailed a chimeric situation by allelic exclusion with almost half of the naive B cell population lacking surface IgD expression. Flow cytometric analyses revealed a distinct phenotype of IgD-negative naive B cells with decreased expression of CD19, CD20 and CD21 as well as lower BAFF-R and integrin-beta 7 expression. IgD-negative B cells were less responsive in vitro after engaging the IgM-BCR, TLR7/9 or CD40 pathway. Additionally, a selective disadvantage of IgD-negative B cells within the T2 transitional and mature naive B cell compartment as well as reduced frequencies of IgM(lo/-) B cells within the mature naive B cell compartment lacking IgD were evident. RNA-Ig-seq of bulk sorted B cell populations showed an altered selection of distinct V-H segments in the IgD-negative mature naive B cell population. We conclude that IgD expression on human naive B cells is redundant for generation of naive B cells in general, but further shapes the naive B cell compartment starting from T2 transitional B cells. Our observations suggest an unexpected role of IgD expression to be critical for selection of distinct Ig V-H segments into the pre-immune Ig repertoire and for the survival of IgM(lo/-) naive B cells known to be enriched in poly-/autoreactive B cell clones.