Abstract
The B cell repertoire is generated in the adult bone marrow by an ordered series of gene rearrangement processes that result in massive diversity of immunoglobulin (Ig) genes and consequently an equally large number of potential specificities for antigen. As the process is essentially random, the cells exhibiting excess reactivity with self-antigens are generated and need to be removed from the repertoire before the cells are fully mature. Some of the cells are deleted, and some will undergo receptor editing to see if changing the light chain can rescue an autoreactive antibody. As a consequence, the binding properties of the B cell receptor are changed as development progresses through pre-B ≫ immature ≫ transitional ≫ naïve phenotypes. Using long-read, high-throughput, sequencing we have produced a unique set of sequences from these four cell types in human bone marrow and matched peripheral blood, and our results describe the effects of tolerance selection on the B cell repertoire at the Ig gene level. Most strong effects of selection are seen within the heavy chain repertoire and can be seen both in gene usage and in CDRH3 characteristics. Age-related changes are small, and only the size of the CDRH3 shows constant and significant change in these data. The paucity of significant changes in either kappa or lambda light chain repertoires implies that either the heavy chain has more influence over autoreactivity than light chain and/or that switching between kappa and lambda light chains, as opposed to switching within the light chain loci, may effect a more successful autoreactive rescue by receptor editing. Our results show that the transitional cell population contains cells other than those that are part of the pre-B ≫ immature ≫ transitional ≫ naïve development pathway, since the population often shows a repertoire that is outside the trajectory of gene loss/gain between pre-B and naïve stages.
Highlights
B cells development starts in the bone marrow (BM), from a hematopoietic stem cell precursor, and undergoes an ordered series of differentiation steps to generate mature naïve B cells in the peripheral blood [1]
The lack of difference between the heavy chain repertoire in pre-B and immature B cells implies that there is very little selective pressure at this developmental stage, which is in agreement with current thinking on the tolerance checkpoints [44]
We do see a major difference between immature BM B cells and the transitional and naïve mature peripheral B cells, where we would expect the repertoire to reflect the changes incurred as a result of the post-immature selective processes that can remove up to 50% of the repertoire [8]
Summary
B cells development starts in the bone marrow (BM), from a hematopoietic stem cell precursor, and undergoes an ordered series of differentiation steps to generate mature naïve B cells in the peripheral blood [1]. Cells without a productive heavy chain gene rearrangement are removed from the repertoire, while cells containing productive heavy chains undergo a few rounds of proliferation and are designated “large” pre-B cells [2]. After this point, light chain recombination of IGK or IGL genes occurs within each cell in order to produce cells with rearranged heavy (IgM) and light chain genes [3,4,5]. The term “transitional cells” was originally coined to categorize the group of early emigrant cells from the BM These cells express IgD and CD10 alongside the IgM BCR so can be identified as IgD+ CD27−CD10hi/+ [9]. The functional classification of CD38hiCD24hicells as transitional cell intermediates between BM and peripheral naïve B cells in development has been complicated by the discovery of human regulatory B cells (Bregs), which are CD38hiCD24hi [18]
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