Whereas T helper cells recognize peptide–major histocompatibility complex (MHC) class II complexes through their T cell receptors (TCRs), CD4 binds to an antigen-independent region of the MHC. Using green fluorescent protein–tagged chimeras and three-dimensional video microscopy, we show that CD4 and TCR-associated CD3ζ cluster in the interface coincident with increases in intracellular calcium. Signaling-, costimulation-, and cytoskeleton-dependent processes then stabilize CD3ζ in a single cluster at the center of the interface, while CD4 moves to the periphery. Thus, the CD4 coreceptor may serve primarily to “boost” recognition of ligand by the TCR and may not be required once activation has been initiated.