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 BRaf 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.The MAP 1 kinase cascade governs multiple cellular processes in T cell function, including proliferation and differentiation. Activation of the MAP kinase ERK (extracellular signalregulated kinase) is required for IL-2 gene transcription and T cell proliferation via engagement of the T cell receptor (TCR) (1). In addition, the magnitude of ERK activation may regulate the response of T cells to TCR engagement (2, 3). Therefore, it is expected that both the magnitude and duration of ERK activation are tightly regulated in T cells.One potential mechanism of ERK regulation is the modulation of Ras signaling by the small G protein, Rap1. Rap1, a member of the Ras super-family, was identified as an antagonist of Ras dependent transformation in fibroblasts (4). In many cell types, including T cells, Rap1 has been shown to inhibit ERK activation by blocking Ras-dependent activation of the MAP kinase kinase kinase, Raf-1 (5-8). Rap1 is activated upon TCR engagement in the absence of costimulation (5, 9, 10) and can limit TCR-induced signals to ERK (5, 11). Interestingly, Rap1 is inhibited by the engagement of the CD28 costimulatory receptor (10, 12), suggesting that one of the functions of Rap1 activation may be to limit ERK activation in the absence of costimulation (5). Indeed, in models of T cell anergy elicited by stimulation through the TCR alone, Rap1 is constitutively active and may limit signaling downstream of Ras (13).Recently other functions of Rap1 have been identified, particularly the enhancement of T cell adhesion (14, 15), raising the possibility that R...