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

Area of Science:

• Immunology
• Cell Biology
• Developmental Biology

Background:

• Natural killer (NK) cells and B cells originate from common lymphoid progenitors.
• The existence and characteristics of cells co-expressing NK and B cell markers (NK-B cells) are debated.
• Previous research has not fully elucidated the developmental pathways and regulatory mechanisms of such hybrid immune cells.

Purpose of the Study:

• To identify and characterize a potentially novel population of NK-B cells.
• To investigate the developmental stage and functional properties of these NK-B cells.
• To elucidate the regulatory pathways governing the survival and function of NK-B cells.

Main Methods:

• Utilized phosphoinositide-dependent protein kinase-1 (PDK1)-deficient mice and wild-type bone marrow.
• Employed single-cell RNA sequencing and high-dimensional flow cytometry for cell identification and characterization.
• Conducted adoptive transfer experiments into lymphocyte-deficient hosts and utilized a novel E4 promoter-binding protein 4 (E4BP4) reporter model.

Main Results:

• Identified a significant population of CD3⁻NKp46⁻CD19⁺NK1.1⁺ cells (NK-B cells) in early B cell developmental stages (pro-B/pre-B).
• Demonstrated that NK-B cells preferentially differentiate into B cells upon adoptive transfer and possess innate characteristics, secreting IFN-γ and TGF-β.
• Revealed that interleukin-15 (IL-15) signaling and Toll-like receptor 9 (TLR9)-mediated sensing of gut microbiota cooperatively sustain E4BP4 expression, crucial for NK-B cell survival.

Conclusions:

• Unveiled a distinct innate-like B cell progenitor pathway characterized by E4BP4 expression.
• Established that this pathway is regulated by the interplay of IL-15 signaling and gut microbiota.
• These findings provide new insights into immune cell development and regulation, highlighting a novel progenitor population with dual innate and adaptive potential.