The most commonly studied IS is that of CD4+ T cells interacting with lymphoma B cells or cytotoxic T cells, that mature into a bull’s eye-like structure formed by three concentrical rings termed supramacromolecular activation centers (SMACs): The cSMAC at the center; the pSMAC, a peripheral ring that surrounds the cSMAC; and the dSMAC, at the edge/distal area of the synapse [8] (Figure 2a). Here, CD4 is linked to lymphoma.