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J. Biol. Chem., Vol. 281, Issue 13, 8559-8564, March 31, 2006

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Tumor Necrosis Factor Receptor (TNFR)-associated Factor 5 Is a Critical Intermediate of Costimulatory Signaling Pathways Triggered by Glucocorticoid-induced TNFR in T Cells^*

Edward M. Esparza, Tullia Lindsten, Julia M. Stockhausen, and Robert H. Arch¹

From the Departments of Medicine and Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri 63110 and the Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Tumor necrosis factor receptor (TNFR) family members such as glucocorticoid-induced TNFR (GITR) control T cell activation, differentiation, and effector functions. Importantly, GITR functions as a pivotal regulator of physiologic and pathologic immune responses by abrogating the suppressive effects of T regulatory cells and costimulating T effector cells. However, the molecular mechanisms underlying GITR-triggered signal transduction pathways remain unclear. Interestingly, GITR-induced stimulation of TNFR-associated factor (TRAF) 5-deficient T cells resulted in decreased activation of nuclear factor B as well as the mitogen-activated protein kinases p38 and extracellular signal-regulated protein kinase, whereas activation of c-Jun N-terminal kinase was less affected. Consistent with impaired signaling, costimulatory effects of GITR were diminished in TRAF5^-/- T cells. In sum, our studies indicate that TRAF5 plays a crucial role in GITR-induced signaling pathways that augment T cell activation.

Received for publication, December 2, 2005 , and in revised form, January 31, 2006.

^* This research was supported in part by National Institutes of Health Grants 5 RO1 HL67312-02 and T32 HL007317 and an Investigator Award of the Cancer Research Institute (to R. H. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Washington University School of Medicine, Campus Box 8052, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-747-4681; Fax: 314-362-9010; E-mail: arch{at}wustl.edu.

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