The c-SMAC: Sorting It All Out (or in)

T cells integrate and transduce the key signals necessary to mount an appropriate immune response. To do this, they rely on both secreted factors as well as physical cell– cell contact. Much attention has focused on the organization of proteins at the contact area between a T cell and an antigen-presenting cell, known as the immunological synapse. It has been shown in vitro that proteins segregate into two distinct regions within this contact area, a central area referred to as the c-SMAC, where the T cell receptor and associated signaling molecules are enriched, and a peripheral region called the p-SMAC containing LFA-1 and the scaffolding protein talin. Whether or not these structures form in vivo and how they function in T cell activation remain issues of great interest. Here, we review recently published work and propose several possible functions for the role of the c-SMAC in T cell activation.