Do T cells need endogenous peptides for activation?

T cells are sensitive to small numbers of antigenic peptide-MHC ligands that are distributed among an excess of endogenous peptide-MHC complexes on the surface of antigen-presenting cells. Although there are accumulating data that indicate a role for these endogenous peptide-MHC complexes in T-cell receptor triggering, whether they are necessary, and the nature of their function, is controversial. In this Opinion article, I argue that endogenous peptide-MHC complexes are required for T-cell stimulation and that their mechanism of action differs between CD4(+) and CD8(+) T cells.