Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling

Daniëls, Mark A.; Teixeiro, Emma; Gill, Jason; Hausmann, Barbara; Roubaty, Dominique; Holmberg, Kaisa; Werlen, Guy; Holländer, Georg A.; Gascoigne, Nicholas R. J.; Palmer, Ed

doi:10.1038/nature05269

Cited by 534 publications

(765 citation statements)

References 50 publications

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“…Last, the localization of Ras/RasGRP1 to the Golgi/plasma membrane was not affected by the number of cognate pMHC-I complexes encountered by CTLs. This mechanism was found to be of importance for inducing anergy through highaffinity binding by the TCR and the binding of a ligand presented in high numbers (25). Combined, our findings suggest that this Agdose induced hyporesponsiveness in CTLs is a distinct form of anergy, whose onset is mechanistically different from the currently described anergic phenotypes or mechanisms shared with thymic selection.…”

Section: Discussioncontrasting

confidence: 37%

“…More specifically, low-affinity binding of epithelial pMHC-I complexes by thymocytes results in the translocation of the Ras-pathway components to the Golgi in a positiveselection process, whereas high-affinity binding induced apoptosis by negative selection through the translocation of Ras-pathway components to the cytoplasm (25). Therefore, we examined the localization of Ras and RasGRP1 to the Golgi as a function of the number of pMHC-I complexes presented on target cells (Fig.…”

Section: Ag-induced Hyporesponsiveness Of Ctls Is Not Dictated By Thementioning

confidence: 99%

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Antigen-Dependent Integration of Opposing Proximal TCR-Signaling Cascades Determines the Functional Fate of T Lymphocytes

Wolchinsky

Hod-Marco

Oved

et al. 2014

The Journal of Immunology

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T cell anergy is a key tolerance mechanism to mitigate unwanted T cell activation against self by rendering lymphocytes functionally inactive following Ag encounter. Ag plays an important role in anergy induction where high supraoptimal doses lead to the unresponsive phenotype. How T cells “measure” Ag dose and how this determines functional output to a given antigenic dose remain unclear. Using multiparametric phospho-flow and mass cytometry, we measured the intracellular phosphorylation-dependent signaling events at a single-cell resolution and studied the phosphorylation levels of key proximal human TCR activation- and inhibition-signaling molecules. We show that the intracellular balance and signal integration between these opposing signaling cascades serve as the molecular switch gauging Ag dose. An Ag density of 100 peptide–MHC complexes/cell was found to be the transition point between dominant activation and inhibition cascades, whereas higher Ag doses induced an anergic functional state. Finally, the neutralization of key inhibitory molecules reversed T cell unresponsiveness and enabled maximal T cell functions, even in the presence of very high Ag doses. This mechanism permits T cells to make integrated “measurements” of Ag dose that determine subsequent functional outcomes.

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Section: Discussioncontrasting

confidence: 37%

Section: Ag-induced Hyporesponsiveness Of Ctls Is Not Dictated By Thementioning

confidence: 99%

Antigen-Dependent Integration of Opposing Proximal TCR-Signaling Cascades Determines the Functional Fate of T Lymphocytes

Wolchinsky

Hod-Marco

Oved

et al. 2014

The Journal of Immunology

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show abstract

“…A currently favored model postulates that the strength, kinetics and compartmentalization of ERK activation dictates the thresholds for both positive and negative selection of thymocytes [9,43,44]. According to this viewpoint, the developmental defect observed in B-Raf -/-thymocytes can be partly explained by the reduction in TCR-mediated ERK activation, which is necessary for thymocytes to pass through the checkpoint of positive selection.…”

Section: Discussionmentioning

confidence: 99%

B‐Raf‐mediated signaling pathway regulates T cell development

et al. 2008

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The activities of the Raf kinase family proteins control extracellular signal-regulated kinase (ERK) activation in many aspects of cellular responses. However, the relative contributions of individual isozymes to cellular functions including T cell responses are still unclear. In addition to Raf-1, another Raf family kinase, B-Raf, is expressed in murine thymocytes and peripheral T cells, and its activation was induced by TCR stimulation. Here, we investigated the function of B-Raf in development of T cells by generating chimeric mice in which a T cell-compromised host was reconstituted with fetal liver-derived cells from embryonic lethal B-Raf-deficient mice. Although B-Raf was dispensable for normal T cell lineage differentiation at the CD4 -CD8 -double-negative stage, thymocytes in the chimeric mice derived from B-Raf -/-cells exhibited a drastic arrest of differentiation at the CD4 + CD8 + double-positive stage, suggesting that B-Raf is crucial for T cell development, especially for the transition to CD4 + and CD8 + singlepositive thymocytes. Regarding intracellular signaling, we found that activation of ERK following TCR stimulation was impaired in the thymocytes from the chimeric mice. In conclusion, we present first evidence for the important role of B-Raf-mediated signaling in T cell development.

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“…Further, we identified Dock2, a guanine nucleotide exchange factor that activates the small G protein Rac (69), and GM130, a Golgi matrix protein, as binding partners for B-Raf and Raf-1. Erk signaling from different locations in a T cell can have different outcomes (70,71), and we contemplate that GM130 might be involved in targeting Raf-1 and B-Raf to the Golgi.…”

Section: Discussionmentioning

confidence: 99%

Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells

Deswal

Meyer

Fiala

et al. 2013

The Journal of Immunology

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The activation kinetics of MAPK Erk are critical for T cell development and activation. In particular, sustained Erk signaling is required for T cell activation and effector functions, such as IL-2 production. Although Raf-1 triggers transient Erk activation, B-Raf is implicated in sustained Erk signaling after TCR stimulation. In this study, we show that B-Raf is dephosphorylated on its inhibitory serine 365 upon TCR triggering. However, it is unknown how B-Raf activation is coupled to the TCR. Using mass spectrometry, we identified protein kinase D–interacting substrate of 220 kDa (Kidins220)/ankyrin repeat-rich membrane spanning protein, mammalian target of rapamycin, Rictor, Dock2, and GM130 as novel B-Raf interaction partners. We focused on Kidins220, a protein that has been studied in neuronal cells and found that it associated with the pre-TCR, αβTCR, and γδTCR. Upon prolonged TCR stimulation, the Kidins220–TCR interaction was reduced, as demonstrated by immunoprecipitation and proximity ligation assays. We show that Kidins220 is required for TCR-induced sustained, but not transient, Erk activation. Consequently, induction of the immediate early gene products and transcription factors c-Fos and Erg-1 was blocked, and upregulation of the activation markers CD69, IL-2, and IFN-γ was reduced. Further, Kidins220 was required for optimal calcium signaling. In conclusion, we describe Kidins220 as a novel TCR-interacting protein that couples B-Raf to the TCR. Kidins220 is mandatory for sustained Erk signaling; thus, it is crucial for TCR-mediated T cell activation.

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Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling

Cited by 534 publications

References 50 publications

Antigen-Dependent Integration of Opposing Proximal TCR-Signaling Cascades Determines the Functional Fate of T Lymphocytes

Antigen-Dependent Integration of Opposing Proximal TCR-Signaling Cascades Determines the Functional Fate of T Lymphocytes

B‐Raf‐mediated signaling pathway regulates T cell development

Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells

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