Constitutive active p21ras enhances primary T cell responsiveness to Ca2+ signals without interfering with the induction of clonal anergy

Crespi, D.; Massa, Stefania; Basso, Veronica; Colombetti, Sara; Mueller, Daniel L.; Mondino, Anna

doi:10.1002/1521-4141(200209)32:9<2500::aid-immu2500>3.0.co;2-s

Cited by 15 publications

(9 citation statements)

References 49 publications

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“…Additional negative regulation of the IL-2 gene at the promoter level independent of upstream signaling has been shown (52)(53)(54). Such additional blocks in anergic cells were invoked by Crespi et al (22) who showed that ERK activation via expression of a constitutively active mutant of Ras was not sufficient to prevent anti-CD3 antibody-induced anergy. Non-physiological activation of the TCR complex by plate-bound antibodies may also account for the inability of Ras-ERK pathways to overcome antibody-induced anergy.…”

Section: Antibody-induced Anergy Cannot Be Prevented By B-raf Expressmentioning

confidence: 99%

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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

Dillon

Karpitski

Wetzel

et al. 2003

Journal of Biological Chemistry

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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...

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Section: Antibody-induced Anergy Cannot Be Prevented By B-raf Expressmentioning

confidence: 99%

“…Recent studies examining the role of ERK inhibition in T cell anergy have utilized constitutively active or interfering mutants of upstream activators of ERKs (22) as well as the pharmacological inhibition of the ERK kinase MEK (23). These manipulations result in the activation or inhibition of ERK without mirroring physiological levels of regulation (24 -26).…”

mentioning

confidence: 99%

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

Dillon

Karpitski

Wetzel

et al. 2003

Journal of Biological Chemistry

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“…Inhibition of AP-1 via negative regulation of Ras might also be essential for maintenance of the anergic state, since introduction of a constitutive active form of Ras into anergic T cells restores IL-2 production and antigen-induced proliferation [52]. On the other hand, there are reports showing that anergy can be induced in T cells transfected with constitutively active Ras [55,56]. IL-2 has been shown to be crucial for cell-cycle entry but also cell-cycle progression from the G 1 to the S phase has been determined as another checkpoint driving T cells towards activation or anergy.…”

Section: Molecular Establishment Of T Cell Anergymentioning

confidence: 99%

Regulation of T Cell Anergy and Escape from Regulatory T Cell Suppression by Cbl‐b

Loeser

Penninger

2009

The Epigenetics of Autoimmune Diseases

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“…It remains unclear, however, whether the MAP kinase cascades are the principal targets of the inhibitory mechanism(s) of anergy, or if this defect is simply a consequence of more upstream inhibition. Indeed, ERK inhibition may be unnecessary for the maintenance of anergy, since primary Tcells retrovirally transduced with constitutively active Ras can still be made anergic using anti-CD3 antibodies [332].…”

Section: The Biochemical Features Of Anergymentioning

confidence: 99%

The Biochemical Mechanisms of T-Cell Anergy

Atfield¹,

Liu²,

Penninger

2006

CIR

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T-cells are thought to play important roles in the coordination and development of immune responses in both health and disease. A key checkpoint in the prevention of inappropriate activation of T-cells is the requirement for costimulation by professional APCs via receptors such as CD28. Several in vivo and in vitro methods of experimental anergy induction have been developed and are in popular use today. However, the biochemical events that determine Tcell fate following the application of activating vs. anergizing stimuli remain poorly understood. We present a survey of T-cell signal transduction in productive encounters with antigen-presenting cells, as well as the molecular mechanisms that are thought to alter these signaling pathways in T-cell anergy and the conceptual and experimental context in which this understanding has been developed. A strong possibility is that the program of anergy induction involves the upregulation of one or more 'anergy factors' and over the years, several possible mechanisms of T-cell anergy have been proposed. Amongst these, E3 ubiquitin ligases such as Cbl-b, Itch and GRAIL have recently emerged as being essential players in T-cell tolerance, as well as host survival.

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Constitutive active p21ras enhances primary T cell responsiveness to Ca2+ signals without interfering with the induction of clonal anergy

Cited by 15 publications

References 49 publications

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

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

Regulation of T Cell Anergy and Escape from Regulatory T Cell Suppression by Cbl‐b

The Biochemical Mechanisms of T-Cell Anergy

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