A schematic representation of regulatory T cell (Treg) immunosuppression by cAMP following gp120 ligation of CD4. Upon triggering of CD4 on Tregs by gp120 protein or possibly by gp120-derived agonists, Lck becomes active and turns on cAMP production by adenylyl cyclase possibly through interaction with a G protein. cAMP is transferred from Treg to effector T cells through cell-to-cell contacts called GAP junctions that allow diffusion of small molecules down the concentration gradient and into effector T cells. Once inside effector cells, cAMP inhibits immune function through PKA–Csk inhibitory pathway that turns off T-cell activation proximally under the T-cell receptor. This could be damaging in HIV, leading to defective anti-HIV immune responses, but a wanted effect when using gp120-derived agonists to modulate the unwanted immunity in tissue rejection or excessive autoimmune responses. Professional illustration by Paulette Dennis.