National Center for
2NAE: Membrane-bound mouse CD28 cytoplasmic tail
Nat. Struct. Mol. Biol. (2017) 24 p.1081-1092
CD28 provides an essential costimulatory signal for T cell activation, and its function is critical in antitumor immunity. However, the molecular mechanism of CD28 transmembrane signaling remains elusive. Here we show that the conformation and signaling of CD28 are regulated by two counteractive charged factors, acidic phospholipids and Ca(2+) ions. NMR spectroscopy analyses showed that acidic phospholipids can sequester CD28 signaling motifs within the membrane, thereby limiting CD28 basal signaling. T cell receptor (TCR) activation induced an increase in the local Ca(2+) concentration around CD28, and Ca(2+) directly disrupted CD28-lipid interaction, leading to opening and signaling of CD28. We observed that the TCR, Ca(2+), and CD28 together form a dual-positive-feedback circuit that substantially amplifies T cell signaling and thus increases antigen sensitivity. This work unravels a new regulatory mechanism for CD28 signaling and thus contributes to the understanding of the dependence of costimulation signaling on TCR signaling and the high sensitivity of T cells.