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