Lck and the nature of the T cell receptor trigger

Davis, Simon J.; Merwe, P. Anton van der

doi:10.1016/j.it.2010.11.003

Cited by 48 publications

(52 citation statements)

References 35 publications

(53 reference statements)

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“…The presence in T cells of a preactivated pool of Lck aided the KS model, as the need for an explanation of the mechanism of Lck activation is obviated [55,56]. However, our estimation of approximately 20-fold lower amount of the fraction of pY394Lck persisting in resting unmanipulated T cells in comparison with a previous report [11] could raise significant discrepancies in the consideration of quantitative aspects of biochemical reactions underpinning T cell activation [55].…”

Section: Discussionmentioning

confidence: 58%

A specific type of membrane microdomains is involved in the maintenance and translocation of kinase active Lck to lipid rafts

et al. 2012

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Section: Discussionmentioning

confidence: 58%

A specific type of membrane microdomains is involved in the maintenance and translocation of kinase active Lck to lipid rafts

et al. 2012

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“…Lck is described to exist in four different phosphorylation states, constantly maintained at equilibrium, with ∼40-50% of consti- tutive active Lck within resting T cells (3,40). As active Lck represents a high risk for a T cell to get permanently activated resulting in hyperreactive adaptive immune reactions in an organism, the spatial arrangement of Lck has to be accurately organized in time and space.…”

Section: Discussionmentioning

confidence: 99%

The Late Endosomal Transporter CD222 Directs the Spatial Distribution and Activity of Lck

Pfisterer

Förster

Paster

et al. 2014

The Journal of Immunology

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The spatial and temporal organization of T cell signaling molecules is increasingly accepted as a crucial step in controlling T cell activation. CD222, also known as the cation-independent mannose 6-phosphate/insulin-like growth factor 2 receptor, is the central component of endosomal transport pathways. In this study, we show that CD222 is a key regulator of the early T cell signaling cascade. Knockdown of CD222 hampers the effective progression of TCR-induced signaling and subsequent effector functions, which can be rescued via reconstitution of CD222 expression. We decipher that Lck is retained in the cytosol of CD222-deficient cells, which obstructs the recruitment of Lck to CD45 at the cell surface, resulting in an abundant inhibitory phosphorylation signature on Lck at the steady state. Hence, CD222 specifically controls the balance between active and inactive Lck in resting T cells, which guarantees operative T cell effector functions.

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“…Therefore, we investigated the effect of big-h3 signaling on the activation of early actors of TCR signaling. Initiation of the TCR signaling pathway relies on the induction of tyrosine protein phosphorylation of the kinase Lck (16,17). The regulation of the enzymatic activity of this Src family tyrosine kinase is tightly controlled by conformational changes mainly relying on phosphorylation and dephosphorylation on two regulatory tyrosine residues, Y505 and Y394 (18,19).…”

Section: Big-h3 Inhibits T-cell Activationmentioning

confidence: 99%

βig-h3 Represses T-Cell Activation in Type 1 Diabetes

et al. 2015

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big-h3/TGF-bi is a secreted protein capable of binding to both extracellular matrix and cells. Human genetic studies recently revealed that in the tgfbi gene encoding for big-h3, three single nucleotide polymorphisms were significantly associated with type 1 diabetes (T1D) risk. Pancreatic islets express big-h3 in physiological conditions, but this expression is reduced in b-cell insult in T1D. Since the integrity of islets is destroyed by autoimmune T lymphocytes, we thought to investigate the impact of big-h3 on T-cell activation. We show here that big-h3 inhibits T-cell activation markers as well as cytotoxic molecule production as granzyme B and IFN-g. Furthermore, big-h3 inhibits early T-cell receptor signaling by repressing the activation of the early kinase protein Lck. Moreover, big-h3-treated T cells are unable to induce T1D upon transfer in Rag2 knockout mice. Our study demonstrates for the first time that T-cell activation is modulated by big-h3, an islet extracellular protein, in order to efficiently avoid autoimmune response.Type 1 diabetes (T1D) is a polygenic autoimmune disease characterized by smoldering inflammatory response directed against the insulin-producing b-islet cells of the pancreas. Both CD4 + and CD8 + T cells are involved in the destruction of b-cells (shed by a prior insult). CD4 + T cells are insulin reactive, and CD8 + T cells play a major role as b-cell killers (1,2). Although both in vitro and in vivo evidence point to a role for regulatory T cells in T-cell-mediated regulation controlling diabetes in mouse models (3), the influence of the inflammatory environment in which they function remains poorly understood. The cross talk between the inflammatory milieu and the immune response during insulitis is likely to be communicated in large part through the extracellular matrix (ECM). big-h3 (also known as TGF-bi) is a secreted protein found in the ECM and it has an N-terminal secretory signal (aa 1-23), four FAS1 homologous internal domains, and a cell attachment site (RGD) at its C terminus (4). big-h3 binds to the ECM through interaction of the YH motif in its FAS1 domains with collagens I, II, IV, and VI (5,6). Its FAS1 domain interacts with its a3b1, aVb3, and aVb5 integrins on the cell surface. Previous studies demonstrated that recombinant big-h3 could preserve the integrity and enhance the function of cultured pancreatic islet cells (7). Conversely, big-h3 knockout (KO) islet function was compromised in vivo after transplantation in recipients with diabetes (8). These studies point out that big-h3 might play an active role in the protection of b-cells against T-cell cytotoxic insult in T1D. The effect of big-h3 on T-cell function and activation relative to its roles in islet b-cell-ECM destruction in T1D in mice has never been investigated and it is the focus of our project. RESEARCH DESIGN AND METHODS MiceFemale C57Bl/6 NOD mice were bred and housed in specific pathogen-free conditions. T1D was chemically induced inC57Bl/6 using a standard low-dose (35 mg/kg) streptozotoci...

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Lck and the nature of the T cell receptor trigger

Cited by 48 publications

References 35 publications

A specific type of membrane microdomains is involved in the maintenance and translocation of kinase active Lck to lipid rafts

A specific type of membrane microdomains is involved in the maintenance and translocation of kinase active Lck to lipid rafts

The Late Endosomal Transporter CD222 Directs the Spatial Distribution and Activity of Lck

βig-h3 Represses T-Cell Activation in Type 1 Diabetes

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