Inducible Costimulator (Icos) Potentiates Tcr-Induced Calcium Flux By Augmenting Plc Gamma 1 Activation And Actin Remodeling

The inducible costimulator (ICOS) is a T cell costimulatory receptor that plays crucial roles in T cell differentiation and function. So far, ICOS has been shown to activate three signaling components: phosphoinositide 3-kinase (PI3K), intracellular calcium mobilization, and TANK binding kinase 1 (TBK1). By generating a knock-in strain of mice in which the ICOS gene is modified such that the ICOS-mediated PI3K pathway is selectively abrogated while the capacity of ICOS to mobilize intracellular calcium remains intact, we have shown that ICOS-mediated PI3K activation is required for some but not all T cell responses. This suggests that the ICOS-calcium signaling axis may explain some of the PI3K-independent ICOS functions. Further, a recent in vivo imaging study indicated that ICOS-dependent intracellular calcium flux facilitates cognate T cell-B cell interactions within the germinal center. However, how ICOS promotes TCR-mediated calcium flux has not been clear. Here we identified a membrane proximal motif in the cytoplasmic tail of ICOS that is essential for ICOS-assisted calcium signaling and demonstrate that ICOS can induce calcium flux independently of other signaling motifs. We also provide evidence that ICOS potentiates phospholipase C gamma 1 (PLC gamma 1) activation to enhance calcium release from the intracellular pool. In parallel, acute ligation of ICOS without TCR co-engagement leads to activation of small GTPases, RhoA and Cdc42, consistent with the capacity of ICOS to induce actin remodeling. Importantly, interruption of actin dynamics during acute TCR or TCR-ICOS co-ligation severely impairs calcium flux in T cells even in the presence of activated PLC gamma 1. Thus, ICOS potentiates TCR-induced calcium flux by enhancing PLC gamma 1 activation and actin remodeling in a coordinated manner. (C) 2016 Elsevier Ltd. All rights reserved.