A self-sustaining layer of early-life-origin B cells drives steady-state IgA responses in the adult gut.

The adult immune system consists of cells that emerged at various times during ontogeny. We aimed to define the relationship between developmental origin and composition of the adult B cell pool during unperturbed hematopoiesis. Lineage tracing stratified murine adult B cells based on the timing of output, revealing that a substantial portion originated within a restricted neonatal window. In addition to B-1a cells, early-life time-stamped B cells included clonally interrelated IgA plasma cells in the gut and bone marrow. These were actively maintained by B cell memory within gut chronic germinal centers and contained commensal microbiota reactivity. Neonatal rotavirus infection recruited recurrent IgA clones that were distinct from those arising by infection with the same antigen in adults. Finally, gut IgA plasma cells arose from the same hematopoietic progenitors as B-1a cells during ontogeny. Thus, a complex layer of neonatally imprinted B cells confer unique antibody responses later in life.

Lin28b controls a neonatal to adult switch in B cell positive selection.

The ability of B-1 cells to become positively selected into the mature B cell pool, despite being weakly self-reactive, has puzzled the field since its initial discovery. Here, we explore changes in B cell positive selection as a function of developmental time by exploiting a link between CD5 surface levels and the natural occurrence of self-reactive B cell receptors (BCRs) in BCR wild-type mice. We show that the heterochronic RNA binding protein Lin28b potentiates a neonatal mode of B cell selection characterized by enhanced overall positive selection in general and the developmental progression of CD5+ immature B cells in particular. Lin28b achieves this by amplifying the CD19/PI3K/c-Myc positive feedback loop, and ectopic Lin28b expression restores both positive selection and mature B cell numbers in CD19-/- adult mice. Thus, the temporally restricted expression of Lin28b relaxes the rules for B cell selection during ontogeny by modulating tonic signaling. We propose that this neonatal mode of B cell selection represents a cell-intrinsic cue to accelerate the de novo establishment of the adaptive immune system and incorporate a layer of natural antibody-mediated immunity throughout life.

Comprehensive Proteomic Characterization of Ontogenic Changes in Hematopoietic Stem and Progenitor Cells.

Hematopoietic stem and progenitor cells (HSPCs) in the fetus and adult possess distinct molecular landscapes that regulate cell fate and change their susceptibility to initiation and progression of hematopoietic malignancies. Here, we applied in-depth quantitative proteomics to comprehensively describe and compare the proteome of fetal and adult HSPCs. Our data uncover a striking difference in complexity of the cellular proteomes, with more diverse adult-specific HSPC proteomic signatures. The differential protein content in fetal and adult HSPCs indicate distinct metabolic profiles and protein complex stoichiometries. Additionally, adult characteristics include an arsenal of proteins linked to viral and bacterial defense, as well as protection against ROS-induced protein oxidation. Further analyses show that interferon α, as well as Neutrophil elastase, has distinct functional effects in fetal and adult HSPCs. This study provides a rich resource aimed toward an enhanced mechanistic understanding of normal and malignant hematopoiesis during fetal and adult life.