Itk is a Critical Regulator of Spatiotemporal Localization at the Immunological Synapse

Date

2010-05-14

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Singleton, Kentner Leroy

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Abstract

The activation of T cells by antigen presenting cells (APCs) is an important step in the initiation of the adaptive immune response. Itk, a member of the Tec family of non-receptor protein tyrosine kinases, is important for T cell activation – Itk-/- CD4+ T cells are hyporesponsive, displaying decreased calcium flux, proliferation, and IL2 production compared to wildtype T cells. The mechanism by which Itk mediates this effect is not fully elucidated. Here we show that Itk is a key regulator of spatiotemporal localization of receptors and proximal signaling intermediates at the T cell / APC interface. As part of this organizational regulation, we found that Itk, through the recruitment of SLAT, mediates activation of Cdc42 at the center of the interface, which is critically required for actin polymerization. We show that targeting activated Cdc42 to the center of the interface restores actin polymerization in the Itk-/- T cell while the addition of constitutively active Cdc42 to the entirety of the interface cannot. These results provide beginnings of a mechanistic explanation of how Itk both regulates the actin cytoskeleton and acts to amplify T cell signaling. These results further demonstrate that control of protein localization at the immunological synapse can be the critical determinant in protein function and that the center of the interface is a site of active signaling.

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