Building an Interleukin‐10‐Producing Identity: How B Cells Acquire Interleukin‐10 Competence and How Plasma Cell Differentiation Consolidates This Program

ABSTRACT Interleukin (IL)‐10‐producing B cells represent an archetype for the regulatory functions of B cells. Here, we review the cell‐surface receptors and transcriptional regulators that control IL‐10 expression in B cells and enable their regulatory function in vivo. To integrate available data, we propose a three‐layer competence–execution–stabilization (CES) framework for IL‐10‐mediated B cell regulation. We propose that B cell receptor signaling during B cell development and at homeostasis contributes to establishing high IL‐10 competence in selected B cell subsets at steady state. Execution of IL‐10 expression and regulatory function then requires the integration of canonical B cell activation pathways with environmental signals and involves transcriptional programs that are largely intertwined with those controlling plasma cell differentiation. Notably, chemically induced IL‐10‐producing B cells progressively differentiate into IL‐10‐producing plasma cells and acquire homogeneous and stable IL‐10 expression. Together with LAG‐3 + CD138 hi plasma cells, these cells represent the only B cell populations described so far in which IL‐10 expression approaches population‐wide penetrance. We therefore propose that plasma cell differentiation may constitute an attractor state for stabilizing IL‐10‐producing regulatory programs. The CES framework provides a conceptual basis for investigating the diversity and regulatory functions of IL‐10‐expressing B cell states in vivo.