ERM family proteins regulate T cell signal initiation by limiting Lck activity and T cell receptor clustering.

Abstract

Abstract Ezrin, radixin, and moesin (ERM) proteins create specialized membrane subdomains by linking phosphatidyl inositol lipids and protein binding partners in the plasma membrane to the underlying actin cortex. These proteins are widely expressed and have well-characterized roles in cell polarity, development, and cytokinesis. In recent years, it has become clear that these proteins are also intimately involved in signal transduction. In humans, mutations in ERM proteins cause severe immunodeficiency characterized by lymphopenia and poor T cell proliferation. To investigate the role of ERM proteins in T cell activation, we generated mice with T cells deficient in ezrin and moesin, the two ERM family members expressed by T cells. Preliminary analysis shows that ERM-deficient CD4+ T cells proliferate poorly in vitro. Interestingly, however, these T cells signal more robustly in response to TCR ligation and produce high amounts of IFNγ. At rest, ERM-deficient T cells exhibit enhanced phosphorylation of Lck and larger pre-clustering of the T cell receptor. These data are consistent with a model in which ERM proteins both maintain cortical actin fences to limit TCR clustering and recruit negative regulators of proximal signaling events to the plasma membrane, thereby governing early events in the TCR signaling cascade.