Abstract
Constitutive Ras signaling has been shown to augment IL-2 production, reverse anergy, and functionally replace many aspects of CD28 co-stimulation in CD4+ T cells. These data raise the possibility that introduction of active Ras into primary T cells might result in improved functionality in pathologic situations of T cell dysfunction, such as cancer or chronic viral infection. To test the biologic effects of active Ras in primary T cells, CD4+ T cells from Coxsackie-Adenovirus Receptor Transgenic mice were transduced with an adenovirus encoding active Ras. As expected, active Ras augmented IL-2 production in naive CD4+ T cells. However, when cells were cultured for 4 days under conditions to promote effector cell differentiation, active Ras inhibited the ability of CD4+ T cells to acquire a Th1 or Th2 effector cytokine profile. This differentiation defect was not due to deficient STAT4 or STAT6 activation by IL-12 or IL-4, respectively, nor was it associated with deficient induction of T-bet and GATA-3 expression. Impaired effector cytokine production in active Ras-transduced cells was associated with deficient demethylation of the IL-4 gene locus. Our results indicate that, despite augmenting acute activation of naïve T cells, constitutive Ras signaling inhibits the ability of CD4+ T cells to properly differentiate into Th1/Th2 effector cytokine-producing cells, in part by interfering with epigenetic modification of effector gene loci. Alternative strategies to potentiate Ras pathway signaling in T cells in a more regulated fashion should be considered as a therapeutic approach to improve immune responses in vivo.
Highlights
The p21 Ras signaling pathway is activated by stimulation of the T cell receptor and plays a critical role in the acute activation of naıve T cells [1,2]
Stimulation of splenic CD4+ T cells with beads coated with antiCD3 and anti-CD28 antibodies resulted in rapid induction of Ras activation and resultant downstream signaling
To determine the effect of active Ras on antigen receptor-induced Ras signaling, both empty vector- and Ras61Ltransduced cells were stimulated with anti-CD3/anti-CD28 mAbcoated beads and ERK phosphorylation was examined
Summary
The p21 Ras signaling pathway is activated by stimulation of the T cell receptor and plays a critical role in the acute activation of naıve T cells [1,2]. In vitro and in silico studies have suggested that strong Ras activation in T cells requires a feedback loop involving both RasGRP and SOS1 while weak or transient Ras activation can be achieved by RasGRP1 alone, without SOS [12,13] In thymocytes, this has led to models in which weak ligands mediate positive selection via RasGRP1induced Ras signaling in the Golgi membrane, while strong ligands induce negative selection via combined RasGRP/SOS1mediated Ras activation at the plasma membrane [14,15]. Additional data from targeted deletion studies suggest that differential Ras signaling during developmental stages in the thymus is mediated by differential Ras GEF expression [7,16,17]
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