Lin28b promotes innate functions in CD8+ T cells through rapid chromatin remodeling

Abstract

Abstract Lin28b serves as a master regulator of fetal lymphopoiesis and promotes the development of more innate-like lymphocytes in early life. However, it is still unclear how Lin28b alters the function of CD8+ T cells and protects the host against infection. In this report we examined how Lin28b transcriptionally and epigenetically programs neonatal CD8+ T cells for innate immune defense. We found that murine neonatal CD8+ T cells possess innate-like transcriptomes, are more responsive to innate cytokines in the absence of antigen and produce a broader spectrum of cytokines compared to their adult counterparts. This unique program of bystander activation in early life corresponded with enhanced innate-like protection against irrelevant strains of bacterial, helminth and virus infections. To understand how this diversity of immune function is mediated, we used flow cytometry and scRNAseq and discovered that the neonatal CD8+ T cell pool is composed of many subsets of cells expressing distinct cytokines. ATACseq analysis revealed that neonatal CD8+ T cells are programmed to display innate-like properties and produce a diverse array of cytokines, which may be due to their ability to undergo extensive chromatin remodeling upon cytokine stimulation. These unique properties may be driven by high Lin28b expression in fetal progenitor cells, as adult cells expressing Lin28b initiated a program of bystander activation and immune protection that was analogous to neonates. Collectively, our data suggests that Lin28b enables neonatal CD8+ T cells to undergo a more diverse program of bystander activation, allowing them to deploy a bet-hedging immune strategy and protect the host against a rapidly changing pathogenic environment.