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

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+CD138hi 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.