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J. Biol. Chem., Vol. 278, Issue 38, 35940-35949, September 19, 2003

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Ectopic B-Raf Expression Enhances Extracellular Signal-regulated Kinase (ERK) Signaling in T Cells and Prevents Antigen-presenting Cell-induced Anergy^*

Tara J. Dillon , Vladamir Karpitski , Scott A. Wetzel ¶, David C. Parker ¶, Andréy S. Shaw  and Philip J. S. Stork  ||

From the Vollum Institute and the ^¶Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, Oregon 97239 and the Department of Pathology and Center for Immunology, Washington University School of Medicine, St Louis, Missouri 63110

T cells that receive stimulation through the T cell receptor (TCR) in the absence of costimulation become anergic and are refractory to subsequent costimulation. This unresponsiveness is associated with the constitutive activation of the small G protein, Rap1, and the lack of Ras-dependent activation of ERK. Recent studies suggest that Rap1 can activate the MAP kinase kinase kinase B-Raf that is either endogenously or ectopically expressed. Peripheral T cells generally do not express B-Raf; therefore, to test the hypothesis that ectopic expression of B-Raf could permit Rap1 to activate ERK signaling, we generated transgenic mice expressing B-Raf within peripheral T cells. This converted Rap1 into an activator of ERK, to enhance ERK activation and proliferation following TCR engagement in the absence of costimulation. When T cells were incubated with engineered APCs presenting antigen on I-E^k and expressing low levels of B7, they became anergic, displayed constitutive activation of Rap1, and were deficient in Ras and ERK activation. However, when incubated with the same APCs, T cells expressing the B-Raf transgene proliferated upon restimulation and displayed elevated ERK activation. Thus B-Raf expression and enhanced ERK activation is sufficient to prevent anergy in a model of APC-induced T cell anergy. However, studies using anti-TCR antibody-induced anergy showed that the ability of ERKs to reverse T cell anergy is dependent on the anergic model utilized.

Received for publication, February 12, 2003 , and in revised form, June 15, 2003.

^* This work was supported by the National Institutes of Health (to D. C. P., A. S. S., and P. J. S. S.; RO1 AI47337) and the Washington-Monsanto Biomedical Research Agreement (to A. S. S.). 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.

^|| To whom correspondence should be addressed: Vollum Institute, L-474, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239-3098. Tel.: 503-494-5494; Fax: 503-494-4976; E-mail: stork{at}ohsu.edu.

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