Density-dependent effects of CD28 cosignaling in vivo. In the peripheral blood T-cell compartment, T cells are at low density, and while they express CD28 the receptor is not competent to transmit signals to trigger cytokine release after ligation by “superagonist” TGN1412. In contrast, in secondary lymphoid organs, T cells reside at higher density and CD28 is competent to release large amounts of TNF-α and other cytokines on ligation. A mechanism suggested for this density-dependent effect may be signals transmitted by MHC class I and II to T-cell receptors.