Costimulation involves reciprocal and sequential signals between cells. A T cell–APC interaction begins when the T cell antigen receptor is stimulated by a specific peptide/MHC complex on the surface of the APC (not shown). Low constitutive levels of B7. 1 and/or B7. 2 on the APC activate CD28 on the T cell, inducing upregulation of CD40L. CD40L in turn binds to CD40 on the APC, enhancing B7. 1/B7. 2 expression and reinforcing the CD28/CD40 positive feedback loop. CD28 costimulation also induces T cell expression of ICOS, allowing a second level of costimulation by APC-expressed ICOSL. Other costimulatory and inhibitory molecules regulated by the initial costimulatory signals (not shown) can further shape the specific outcome of the interaction.