CD25 recruits inhibitory phosphatases for feedback control of B-cell receptor signaling

Abstract Successful initiation of the B-cell receptor (BCR) signaling, and subsequent antigen-encounter in germinal centers are both marked by sharp increases of CD25 surface-expression. Likewise, oncogenic signaling in B-cell leukemia (B-ALL) and lymphoma induces CD25-surface expression. While CD25 is known as an IL2-receptor chain on T- and NK-cells, the significance of its expression on B-cells was unclear. We discovered that, rather than functioning as an IL2-receptor chain, CD25 expressed on B-cells feedback regulates BCR-signaling or its oncogenic mimics. Recapitulating phenotypes of genetic ablation of PKCD, SHIP1 and SHP1, conditional CD25-deletion suppressed early B-cell development but induced hyperactivation of antigen-experienced B-cells and autoimmunity. Additionally, B-cell-specific CD25 deletion resulted in formation of spontaneous germinal centers and expansion of autoreactive B cells. Biochemical and interactome studies revealed that BCR-signaling induced PKCd-dependent CD25-phosphorylation of the CD25 cytoplasmic tail (S268) to recruit inhibitory phosphatases to the BCR complex. Upon CD25-deletion, SHIP1 and SHP1 were no longer recruited and activated to limit duration and strength of BCR-signaling. Loss of phosphatase-function, autonomous BCR-signaling and Ca 2+-oscillations induced anergy and negative selection during early B-cell development, as opposed to proliferation and autoantibody production in antigen-experienced B-cells. These findings highlight the previously unrecognized role of CD25 in assembling inhibitory phosphatases to prevent chronic BCR signaling and safeguard B cell tolerance.