Ikaros Enforces the Costimulatory Requirement for <i>IL2</i> Gene Expression and Is Required for Anergy Induction in CD4+ T Lymphocytes

Thomas, Robin; Chunder, Neelanjana; Chen, Chunxia; Umetsu, Sarah E.; Winandy, Susan; Wells, Andrew D.

doi:10.4049/jimmunol.179.11.7305

Cited by 88 publications

(135 citation statements)

References 78 publications

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“…45,46 Therefore, drug-induced disruption of this axis in T cells may explain the poly-lineage effects that we observed. Analysis of serial samples identified rebound in IKZF1 levels in immune cells with ongoing therapy, which may represent a mechanism of acquired resistance to drug-induced immune activation.…”

Section: Discussionmentioning

confidence: 80%

Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets

Sehgal¹,

Das²,

Zhang³

et al. 2015

Blood

108

100

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Section: Discussionmentioning

confidence: 80%

Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets

Sehgal¹,

Das²,

Zhang³

et al. 2015

Blood

108

100

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“…In addition, epigenetic silencing of the IL-2 locus may contribute to the impaired IL-2 production in anergic T cells (45). In TSC1KO T cells, Egr2/3, Itch, Grail, and Cbl-b expression is down-regulated compared with WT T cells following induction of anergy, suggesting that TSC1 may promote T-cell anergy through up-regulation of these anergy-inducing molecules.…”

Section: Discussionmentioning

confidence: 99%

Tumor suppressor TSC1 is critical for T-cell anergy

Xie

Lou

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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T-cell anergy is a state of T cells that is hyporesponsive to stimulation via the T-cell receptor and costimulatory molecules and is thought to be important for self-tolerance. How T-cell anergy is regulated is still poorly understood. We report here that tuberous sclerosis (TSC)1 is critical for T-cell anergy. Deficiency of TSC1 resulted in enhanced Tcell proliferation and cytokine production in the absence of cluster of differentiation (CD)28-mediated costimulation, accompanied by enhanced T-cell metabolism. Resistance of TSC1-deficient T cells to anergy is correlated with increased signaling through the mammalian target of rapamycin complex (mTORC)1 and can be reverted by treatment of these cells with mTORC1 inhibitor rapamycin. Expression of the inducible costimulator (ICOS) is increased in TSC1-deficient T cells, which can be inhibited by rapamycin. Simultaneous blockade of both CD28 and ICOS costimulation partially restored sensitivity of TSC1-deficient T cells to anergy induction. Together, our data indicate that TSC1 is crucial for T-cell anergy by inhibiting mTORC1 signaling through both ICOS-dependent and -independent mechanisms.T-cell activation | signal transduction C oordinated signals from the T-cell receptor (TCR), costimulatory receptors, and cytokine receptors ensure naïve T-cell activation and differentiation to proper effector T cells. T cells can be made anergic by stimulation through their TCR without a costimulatory signal, by stimulation with partial agonist peptides in the presence of costimulation, or by treatment with the Ca 2+ ionophore ionomycin (1-3). Anergic T cells do not respond to antigen restimulation even in the presence of appropriate costimulation. They are impaired in producing cytokines such as IFN-γ or IL-2, defective in proliferative response, and metabolically inert (4-7). T-cell anergy is thought to be important for preventing self-reactive T cells from full activation to trigger autoimmune diseases.The mammalian target of rapamycin (mTOR) integrates numerous environmental stimuli including growth factors, nutrients, and stress-activated signals to regulate cell metabolism, survival, growth, and proliferation (8). mTOR associates with multiple proteins and forms two distinct signaling complexes. mTOR complex (mTORC)1 contains raptor and phosphorylates ribosomal protein s6 kinase, 70-kd, 1 (S6K1) and eukaryotic translation initiation factor 4e-binding protein 1 (4E-BP1) to promote ribosomogenesis and protein translation. The rictor-containing mTORC2 phosphorylates both Akt at serine 473 residue to promote Akt activation and cell survival and PKCθ to promote T-helper (Th)2 differentiation (9, 10). Engagement of the TCR activates both mTORC1 and mTORC2, which is dependent on the RasGRP1-Ras-Erk1/2 pathway and is inhibited by diacylglycerol kinases (11-13). Rapamycin treatment or genetic ablation of mTOR induces T-cell anergy and inhibits helper T-cell differentiation but promotes expansion of natural regulatory T cells (nTregs) and the generation of inducible Tregs (9, 14-...

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“…Previous studies have identified several genes that are upregulated in anergic CD4 + T cells when there is NFAT but not AP-1 transcriptional activation (20)(21)(22)(23)(24)(25)(26)(27). We therefore determined whether Sirt1, as a HDAC, induces and/or maintains CD4 + T cell tolerance by altering the expression of these anergic genes.…”

Section: Sirt1 Suppresses T Cell-dependent Immunity In Micementioning

confidence: 97%

The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice

Zhang¹,

Lee²,

Shannon³

et al. 2009

J. Clin. Invest.

263

286

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Although many self-reactive T cells are eliminated by negative selection in the thymus, some of these cells escape into the periphery, where they must be controlled by additional mechanisms. However, the molecular mechanisms underlying peripheral T cell tolerance and its maintenance remain largely undefined. In this study, we report that sirtuin 1 (Sirt1), a type III histone deacetylase, negatively regulates T cell activation and plays a major role in clonal T cell anergy in mice. In vivo, we found that loss of Sirt1 function resulted in abnormally increased T cell activation and a breakdown of CD4 + T cell tolerance. Conversely, upregulation of Sirt1 expression led to T cell anergy, in which the activity of the transcription factor AP-1 was substantially diminished. Furthermore, Sirt1 interacted with and deacetylated c-Jun, yielding an inactive AP-1 factor. In addition, Sirt1-deficient mice were unable to maintain T cell tolerance and developed severe experimental allergic encephalomyelitis as well as spontaneous autoimmunity. These findings provide insight into the molecular mechanisms of T cell activation and anergy, and we suggest that activators of Sirt1 may be useful as therapeutic agents for the treatment and/or prevention of autoimmune diseases.

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Ikaros Enforces the Costimulatory Requirement for IL2 Gene Expression and Is Required for Anergy Induction in CD4+ T Lymphocytes

Cited by 88 publications

References 78 publications

Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets

Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets

Tumor suppressor TSC1 is critical for T-cell anergy

The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice

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