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

Temporally restricted expression of Lin28b promotes generation of self-reactive B-1 cells early in life. Sending B cells back in time B-1 cells are a subset of self-reactive B cells that arise in early life. Precisely how and why the immune system permits the development of self-reactive B cells in neonates remains a mystery. Here, by studying B cell development in neonatal mice, Vanhee et al. have uncovered the importance of RNA binding protein Lin28b in facilitating positive selection of self-reactive B-1 cells in neonates. Further, they found that ectopic expression of Lin28b was sufficient to promote selection of self-reactive B-1 cells in adult mice. The authors propose that Lin28b functions as a cell-intrinsic switch that jumpstarts the generation of B cells in early life. 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.

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