(A) A new PD-1H–centric model. PD-1H on the surface of T cells and APCs interacts with an unknown receptor(s) on T cells to directly inactivate T cells and confer immune suppression. (B) Classic models of immune activation and immune suppression through modulation of costimulatory activity of APCs. For immune activation, interaction of CD40L expressed on Th cells with CD40 on APCs induces expression of costimulatory molecules, including CD86 and others. The T cells that recognize the same APCs are activated as they are provided with both signal 1 (S1), the cognate antigens (MHC plus peptide [MHCp]), and signal 2 (S2), the costimulatory signal. During immune suppression, Tregs use CTLA-4 to rip CD28 ligands from the surface of APCs. The T cells that recognize the same APC are suppressed as they are provided with only S1, which inactivates T cells through death and anergy (17, 18).