NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins

T cell receptor ( TCR) and costimulatory receptor ( CD28) signals cooperate in activating T cells, although understanding of how these pathways are themselves regulated is incomplete. We found that Homer2 and Homer3, members of the Homer family of cytoplasmic scaffolding proteins, are negative regulators of T cell activation. This is achieved through binding of nuclear factor of activated T cells ( NFAT) and by competing with calcineurin. Homer-NFAT binding was also antagonized by active serine- threonine kinase AKT, thereby enhancing TCR signaling via calcineurin- dependent dephosphorylation of NFAT. This corresponded with changes in cytokine expression and an increase in effector- memory T cell populations in Homer- deficient mice, which also developed autoimmune- like pathology. These results demonstrate a further means by which costimulatory signals are regulated to control self- reactivity.