NFAT Binding and Regulation of T Cell Activation by the Cytoplasmic Scaffolding Homer Proteins

;
• Huso, David L.
;
• Bouyain, Samuel
;
• Tu, Jianchen
;
• McCorkell, Kelly A.
;
• May, Michael J.
;
• Zhu, Yuwen
;
• Lutz, Michael
;
• Collins, Samuel
;
• Dehoff, Marlin
;
• Kang, Shin
;
• Whartenby, Katharine
;
• Powell, Jonathan
;
• Leahy, Daniel
;
• Worley, Paul F.

Abstract

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.