T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-α

Zha, Yuanyuan; Marks, Reinhard; Ho, Allen W.; Peterson, Amy; Janardhan, Sujit; Brown, Ian E.; Praveen, Kesavannair; Stang, Stacey L.; Stone, James C.; Gajewski, Thomas F.

doi:10.1038/ni1394

Cited by 258 publications

(287 citation statements)

References 42 publications

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“…Two independent investigators have observed that diacylglycerol kinase-α (DGK-α) is upregulated in anergic T cells [65,66], indicating that there is a link between the TCR signaling molecule DAG and T cell responsiveness. As depicted in Fig.…”

Section: Role Of Signaling Molecules In T Cell Hyporesponsivenessmentioning

confidence: 99%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

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Section: Role Of Signaling Molecules In T Cell Hyporesponsivenessmentioning

confidence: 99%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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“…The ERK kinases overcome SHP-1 phosphatase blockade of proximal T cell receptor (TCR) signaling (5), and more globally, influence the maturation of T cells in the thymus (6 -9) and production of interleukin-2 (IL-2) in the post-thymic peripheral T cells (10 -14). The observation that a relative lack of Ras/ERK signal is associated with inability of T cells to respond to an antigen further underscores the fundamental role of this signaling pathway in T cell stimulation (15)(16)(17). It is not surprising to find therefore that T cells and other cell types have developed inhibitors to control the magnitude and duration of the ERK signaling.…”

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confidence: 99%

p21 Ras/Impedes Mitogenic Signal Propagation Regulates Cytokine Production and Migration in CD4 T Cells

Czyzyk

Chen

Bottomly

et al. 2008

Journal of Biological Chemistry

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The propensity of T cells to generate coordinated cytokine responses is critical for the host to develop resistance to pathogens while maintaining the state of immunotolerance to selfantigens. The exact mechanisms responsible for preventing the overproduction of proinflammatory cytokines including interferon (IFN)-␥ are not fully understood, however. In this study, we examined the role of a recently described Ras GTPase effector and repressor of the Raf/MEK/ERK cascade called impedes mitogenic signal propagation (Imp) in limiting the induction of T-cell cytokines. We found that stimulation of the T cell receptor complex leads to the rapid development of a physical association between Ras and Imp. Consistent with the hypothesis that Imp inhibits signal transduction, we also found that disengagement of this molecule by the Ras V12G37 effector loop mutant or RNA interference markedly enhances the activation of the NFAT transcription factor and IFN-␥ secretion. A strong output of IFN-␥ is responsible for the distinct lymphocyte traffic pattern observed in vivo because the transgenic or retroviral expression of Ras V12G37 caused T cells to accumulate preferentially in the lymph nodes and delayed their escape from the lymphoid tissue, respectively. Together, our results describe a hitherto unrecognized negative regulatory role for Imp in the production of IFN-␥ in T cells and point to Ras-Imp binding as an attractive target for therapeutic interventions in conditions involving the production of this inflammatory cytokine.The small GTPase Ras is a potent signaling molecule that can bind with numerous downstream effector molecules including the protein kinase Raf (1, 2). Raf in turn activates the mitogenactivated protein kinase (MAPK) 2 kinase (MEK)/extracellular signal-regulated kinase (Erk) cascade (3, 4). This signaling pathway controls many pivotal functions in T cells. The ERK kinases overcome SHP-1 phosphatase blockade of proximal T cell receptor (TCR) signaling (5), and more globally, influence the maturation of T cells in the thymus (6 -9) and production of interleukin-2 (IL-2) in the post-thymic peripheral T cells (10 -14). The observation that a relative lack of Ras/ERK signal is associated with inability of T cells to respond to an antigen further underscores the fundamental role of this signaling pathway in T cell stimulation (15-17). It is not surprising to find therefore that T cells and other cell types have developed inhibitors to control the magnitude and duration of the ERK signaling. Among the most prominent endogenous repressors of the Ras/ERK signaling are GTPase-activating proteins (18, 19), downstream of tyrosine kinase (Dok) adaptor proteins (20 -22), members of the Sprouty protein family (23, 24), diacylglycerol kinases (DGK-and DGK-␣) (25, 26), ERK-specific dual specificity phosphatases (27), and a molecule with an E3 ubiquitin ligase activity described recently as impedes mitogenic signal propagation (Imp) (28).Imp, also known as BRCA1-associated protein (BRAP2), was originally identified as a...

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“…Ras and Erk1/2 have been implicated in both positive selection and negative selection (12-17). Recent evidence indicates that DGK␣ and , isoforms known to be expressed in T cells negatively control DAG and the Ras-Erk1/2 signaling pathway after TCR engagement (18)(19)(20)(21)(22). Deficiency of either DGK␣ or causes enhanced T cell activation and resistance to anergy induction (19,20).…”

mentioning

confidence: 99%

Synergistic control of T cell development and tumor suppression by diacylglycerol kinase α and ζ

Guo

Wan

Carpenter

et al. 2008

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

110

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Diacylglycerol (DAG) kinases (DGKs) are a family of enzymes that convert DAG to phosphatidic acid (PA), the physiologic functions of which have been poorly defined. We report here that DGK ␣ and synergistically promote T cell maturation in the thymus. Absence of both DGK␣ and (DGK␣ ؊/؊ ؊/؊ ) results in a severe decrease in the number of CD4 ؉ CD8 ؊ and CD4 ؊ CD8 ؉ single-positive thymocytes correlating with increased DAG-mediated signaling. Positive selection, but not negative selection, is impaired in DGK␣ ؊/؊ ؊/؊ mice. The developmental blockage in DGK␣ ؊/؊ ؊/؊ mice can be partially overcome by treatment with PA. Furthermore, decreased DGK activity also promotes thymic lymphomagenesis accompanying elevated Ras and Erk1/2 activation. Our data demonstrate a synergistic and critical role of DGK isoforms in T cell development and tumor suppression, and indicate that DGKs not only terminate DAG signaling but also initiate PA signaling in thymocytes to promote positive selection.phosphatidic acid ͉ signaling ͉ tumorigenesis D iacylglycerol (DAG) kinases (DGKs) are a family of enzymes that catalyze phosphorylation of DAG, converting it to phosphatidic acid (PA). Ten DGK isoforms have been identified in mammals and are divided into 5 subtypes based on unique structural features (1, 2). Within a single tissue, multiple DGK isoforms can be expressed. A notable feature of the DGK-mediated reaction is that both the substrate, DAG, and the product, PA, can be important second messengers. DAG can associate with Ras guanyl nucleotide-releasing proteins (RasGRPs), protein kinase Cs (PKCs), protein kinase Ds, chimaerins, and Munc-13s through their cysteine-rich (C1) domains (3). PA has been reported to bind to the SH-2 domain containing tyrosine phosphatase-1 (SHP-1), mammalian target of Rapamycin (mTOR), cAMP-specific phosphodiesterase 4 (PDE4), protein phosphatase-1 (PP-1), son of sevenless (Sos), and type I phosphatidylinositol 4-phosphate 5-kinase (PI5K) (4 -8). Through the regulation of the activities and subcellular localizations of these signaling molecules, DAG and PA play critical roles in signaling from many cell surface receptors (3, 4). It has been hypothesized that DGKs act as crucial regulators of receptor signaling and cellular function by modulating DAG and PA concentrations. However, the physiologic importance of most DGKs and the role of DGK-derived PA in receptor signaling have been poorly defined.T cell maturation in the thymus occurs through CD4 Ϫ CD8 Ϫ double-negative (DN) to CD4 ϩ CD8 ϩ double-positive (DP) and finally to the CD4 ϩ CD8 Ϫ or CD4 Ϫ CD8 ϩ single-positive (SP) stage (9). Engagement of TCR expressed on DP thymocytes with self-peptide presented by MHCs on thymic stromal cells and bone marrow-derived dendritic cells induces intracellular signaling that can lead to either maturation (positive selection) or cell death (negative selection). In general, TCRs with high affinity to self-antigens elicit strong signals directing negative selection, whereas TCRs with low affinity to self-antigens induce...

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T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-α

Cited by 258 publications

References 42 publications

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

p21 Ras/Impedes Mitogenic Signal Propagation Regulates Cytokine Production and Migration in CD4 T Cells

Synergistic control of T cell development and tumor suppression by diacylglycerol kinase α and ζ

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