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Science 319 (5862): 476-481

Copyright © 2008 by the American Association for the Advancement of Science

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

Guo N. Huang,1,2* David L. Huso,3{dagger} Samuel Bouyain,4{dagger} Jianchen Tu,2{dagger} Kelly A. McCorkell,5{dagger} Michael J. May,5 Yuwen Zhu,6 Michael Lutz,7 Samuel Collins,7 Marlin Dehoff,2 Shin Kang,2 Katharine Whartenby,7 Jonathan Powell,7 Daniel Leahy,4 Paul F. Worley2,8{ddagger}

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.

1 Program in Biochemistry, Cellular and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3 Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4 Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5 Department of Animal Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
6 Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
7 Department of Oncology-Immunology/Hematopoiesis, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
8 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

* Present address: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.

{dagger} These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: pworley{at}jhmi.edu


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