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Cutting Edge: Requirement for TRAF6 in the Induction of T Cell Anergy¹

Carolyn G. King^*, Jodi L. Buckler, Takashi Kobayashi^*, Jeffrey R. Hannah^*, Garrett Bassett^*, Taesoo Kim^*, Erika L. Pearce^*, Gregory G. Kim^*, Laurence A. Turka and Yongwon Choi^2,*

^* Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

TRAF6, TNFR-associated factor 6, is a key adaptor downstream from the TNF receptor and TLR superfamily members. T cell-specific deletion of TRAF6 (TRAF6-T) was recently shown to result in the development of multiorgan inflammatory disease and the resistance of responder T cells to suppression by CD4⁺CD25⁺ regulatory T cells. In this study we examined the role of TRAF6 in an additional mechanism of peripheral tolerance, anergy. We have determined that the loss of TRAF6 restores the ability of CD28^–/– T cells to proliferate and produce IL-2. Consistent with this, TRAF6-T T cells were resistant to anergizing signals both in vitro and in vivo. Resistance to anergy was correlated with decreased expression of Cbl-b. These findings reveal that in addition to its role in rendering T cells susceptible to control by CD4⁺CD25⁺ regulatory T cells, TRAF6 is essential for the induction of T cell anergy, implicating TRAF6 as a critical mediator of peripheral tolerance.

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 This work was supported in part by National Institutes of Health Grant AI-43620 (to Y.C. and L.A.T.).

² Address correspondence and reprint requests to Dr. Yongwon Choi, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Room 308, Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6144. E-mail address: ychoi3{at}mail.med.upenn.edu

³ Abbreviations used in this paper: TRAF6, TNFR-associated factor 6; SEB, staphylococcal enterotoxin B; TRAF6-T, T cell-specific deletion of TRAF6.

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