Mechanotransduction governs CD40 function and underlies X-linked Hyper IgM syndrome

Abstract

B cell maturation in germinal centers (GCs) depends on cognate interactions between the T and B cells. Upon interaction with CD40 ligand (CD40L) on T cells, CD40 delivers co-stimulatory signals alongside B cell antigen receptor (BCR) signaling to regulate affinity maturation and antibody class-switch during GC reaction. Mutations in CD40L disrupt interactions with CD40, which lead to abnormal antibody responses in immune deficiencies known as X-linked Hyper IgM syndrome (X-HIgM). Assuming that physical interactions between highly mobile T and B cells generate mechanical forces on CD40–CD40L bonds, we set out to study the B cell mechanobiology mediated by CD40–CD40L interaction. Using a suite of biophysical assays we find that CD40 forms catch bond with CD40L where the bond lasts longer at larger forces, B cells exert tension on CD40–CD40L bonds, and force enhances CD40 signaling and antibody class-switch. Significantly, X-HIgM CD40L mutations impair catch bond formation, suppress endogenous tension, and reduce force-enhanced CD40 signaling, leading to deficiencies in antibody class switch. Our findings highlight the critical role of mechanotransduction in CD40 function and provide insights into the molecular mechanisms underlying X-HIgM syndrome.

Switching circuits: Modulating NK cell response to TGF-β using novel receptors

“…The molecular mechanism of switch receptor activation was not evaluated here, but the validated switches included domains that are capable of two distinct modes of signal transduction: 1) mechanotransduction (e.g. 4-1BB, CD40 15 ) or 2) homodimerization (e.g. IL-7R 16 ).…”