T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-a
T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-α
Nat. immunol. 7, 1166-1173 (2006)
Speaker: 張有德 Time: 14:00-15:00; Dec 6, 2006
Commentator: 林以行老師 Place: room 601
Abstract:
Anergy is a hypo-responsive state induced by incomplete stimulation of T cells which is mediated by T cell receptor (TCR) without co-stimulatory factor CD28. Anergic T cells are defective in producing interleukin-2 (IL-2) and show reduced proliferation after stimulation via TCR and CD28. Although the molecular mechanism underlying T cell anergy is still unknown, some correlations between T cell anergy and Ras have been established1. The authors transduced the adenovirus encoding constitutively active Ras mutant Ras61L into the anergic T cells from the coxsackie and adenovirus receptor (CAR)-transgenic mice and found that Ras61L restored IL-2 production and MAP kinase activation in the anergic T cell either made in vitro or in vivo. It is known that anergy is mediated by increased recruitment of the complex containing the Crk-like (CrkL) adaptor protein to thplasma membrane via the Casitas B lineage lymphoma (Cbl) E3 ubiquitin ligase2. To identify the mechanism by which Ras activation is blunted during anergy, the authors analyzed the Th1 clones from CrkL-deficient mice and CAR-Th1 cells expressing dominant negative Cbl to exclude the absolute requirement of CrkL and Cbl for the induction or maintenance of T cell anergy. Moreover, the authors identified diacylglycerol kinase-α (DGK-α) as the candidate regulator of Ras activation in anergic T cells by gene screening. Overexpression of DGK-α in Th1 cells resulted in the phenotype of anergy after CD3 and CD28 stimulation, including reduction of IL-2 production, suppression of Jnk and Erkphosphorylation, inhibited IL-2 promoter activity and defective RasGRP-1 translocation. Treating 2C T cells made anergy in vivo with DGK inhibitor recovered it’s IL-2 production and confirmed the role of DGK in anergy.
References:
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2. Boussiotis V. A., Freeman G. J., Berezovskaya A., Barber D. L., Nadler L. M. Maintenance of human T cell anergy: blocking of IL-2 gene transcription by activated Rap1.Science 278, 124-128 (1997)