GSE135649
An ontogenetic switch in the positive and negative selection of B cells [B cell subsets]
Developing B cells can differentiate into a variety of different subsets, but the mechanisms that determine these outcomes are incompletely understood, with theories based on separate lineages or the positive and negative selection by self-antigens.  In particular, the development of the B-1 B cell subset arises mainly from precursors in early ontogeny and is subject to positive selection by self-antigens, whereas the follicular B-2 B cell subset arises later and is subject to negative control. In this study we show how a cell intrinsic switch from Lin28b to Let7 gene expression changes a B cell's susceptibility from positive to negative selection during ontogeny. Ectopic expression of a Lin28b transgene in B cells restores the positive selection of autoreactive B-1 B cells by self-antigen in adult bone marrow.  Analysis of antigen-specific immature B cells in early and late ontogeny identifies Lin28b-dependent genes associated with B-1 B cell development, including Arid3a and Bhleh41, and Lin28b-independent effects associated with the presence or absence of self-antigen. These findings identify cell intrinsic and extrinsic determinants of B cell fate during ontogeny and reconcile lineage and selection theories of B cell development. They explain how changes in the balance of positive and negative selection may be able to adapt to meet the immunological needs of an individual during its lifetime. Overall design: Examination of the transcriptome from B cells isolated from peripheray (B cell subsets A:anergic,B:Follicular,C:MZ B cell, D: B1 B cell)