# A Microbiota‐ and IL‐15‐Dependent Innate‐Like B Cell Progenitor Expressing E4BP4

## TL;DR

This study discovers a unique type of B cell progenitor with innate immune features that depends on gut microbiota and IL-15 signaling for its development.

## Contribution

Identifies a novel E4BP4-expressing, microbiota- and IL-15-dependent innate-like B cell progenitor pathway.

## Key findings

- NK-B cells are enriched in PDK1-deficient mice and present in wild-type bone marrow.
- IL-15 and TLR9-microbiota signaling sustain E4BP4 expression in these progenitors.
- Germ-free and IL-15/E4BP4-deficient mice show a significant loss of NK-B cells.

## Abstract

While natural killer (NK) cells and B cells arise from common lymphoid progenitors, the existence and nature of cells co‐expressing markers of both lineages (NK‐B cells) remain controversial. Here, this work identifies a significant population of CD3−NKp46−CD19⁺NK1.1⁺ cells, termed NK‐B cells, enriched in phosphoinositide‐dependent protein kinase‐1(PDK1)‐deficient mice but also present in wild‐type bone marrow. Single‐cell RNA sequencing and high‐dimensional flow cytometry reveal these NK‐B cells reside within early B cell developmental stages (pro‐B/pre‐B). Functionally, upon adoptive transfer into lymphocyte‐deficient hosts, NK‐B cells preferentially differentiated into B cells. Unlike conventional B cell precursors, NK‐B cells exhibit innate characteristics, including the capacity to secrete interferon‐gamma (IFN‐γ) and transforming growth factor‐beta (TGF‐β), and expressed CD122 (IL‐2/15Rβ) and Toll‐like receptor 9 (TLR9). Using a novel E4 promoter‐binding protein 4 (E4BP4) reporter model, this work demonstrates that both interleukin‐15 (IL‐15) signaling (via CD122) and TLR9‐mediated sensing of the gut microbiota cooperatively sustain E4BP4 expression within these progenitors. Consequently, germ‐free mice and mice deficient in IL‐15 or E4BP4 exhibit a profound loss of NK‐B cells. These findings unveil a distinct E4BP4‐expressing, innate‐like B cell progenitor pathway regulated by microbiota and IL‐15.

This work identifies CD3.NKp46.CD19.NK1.1. NK‐B cells enriched in PDK1‐deficient yet present in wild‐type bone marrow. IL‐15 (via CD122) and TLR9‐microbiota signaling maintain their E4BP4 expression. These cells demonstrate innate immunity, preferentially differentiate into B cells, and unveil a novel microbiota‐ and IL‐15‐dependent regulatory pathway in lymphopoiesis.