IKK promotes naïve T cell survival by repressing RIPK1-dependent apoptosis and activating NF-κB

The inhibitor of κB kinase (IKK) complex regulates the activation of the nuclear factor κB (NF-κB) family of transcription factors. In addition, IKK represses extrinsic cell death pathways dependent on receptor-interacting serine/threonine-protein kinase 1 (RIPK1) by directly phosphorylating this kinase. Here, we showed that peripheral naïve T cells in mice required the continued expression of IKK1 and IKK2 for their survival; however, the loss of these cells was only partially prevented when extrinsic cell death pathways were blocked by either deleting Casp8 (which encodes the apoptosis-inducing caspase 8) or inhibiting the kinase activity of RIPK1. Inducible deletion of Rela (which encodes the NF-κB p65 subunit) in mature CD4+ T cells also resulted in loss of naïve CD4+ T cells and in reduced abundance of the interleukin-7 receptor (IL-7R) encoded by the NF-κB target Il7r, revealing an additional reliance upon NF-κB for the long-term survival of mature T cells. Together, these data indicate that the IKK-dependent survival of naïve CD4+ T cells depends on both repression of extrinsic cell death pathways and activation of an NF-κB-dependent survival program

Hedgehog Signalling in the Embryonic Mouse Thymus

T cells develop in the thymus, which provides an essential environment for T cell fate specification, and for the differentiation of multipotent progenitor cells into major histocompatibility complex (MHC)-restricted, non-autoreactive T cells. Here we review the role of the Hedgehog signalling pathway in T cell development, thymic epithelial cell (TEC) development, and thymocyte–TEC cross-talk in the embryonic mouse thymus during the last week of gestation

IFITM proteins drive type 2 T helper cell differentiation and exacerbate allergic airway inflammation

T cells differentiated more efficiently to Th1, whereas Th2 differentiation was inhibited. Ifitm-family-deficient mice, but not Ifitm3-deficient mice, were less susceptible than WT to induction of allergic airways disease, with a weaker Th2 response and less severe disease and lower Il4 but higher Ifng expression and IL-27 secretion. Thus, the Ifitm family is important in adaptive immunity, influencing Th1/Th2 polarization, and Th2 immunopathology

Variational theory of complex rays applied to shell structures: in-plane inertia, quasi-symmetric ray distribution, and orthotropic materials

International audienceRecently, interest of aerospace and automotive industries on medium-frequency vibrational behavior of composite shell structures has grown due to their high specific stiffness and fatigue resistance. Conventional methods such as the finite element method and the statistical energy analysis are not suitable for the medium-frequency bandwidth. Conversely, the variational theory of complex rays (VTCR) is taking place as an ad-hoc technique to tackle such frequency band. It is a Trefftz method based on a weak variational formulation. Equilibrium equations are met using exact solutions as shape functions. The variational problem imposes boundary conditions in weak form. The present paper extends VTCR to orthotropic shell structures. Moreover, several new enhancements are introduced. Now, we use a quasi-symmetric ray distribution which can greatly reduce computational costs, and addresses in-plane inertia which was neglected in previous works. Some relevant numerical examples are presented to show the strategy and results are compared with a FEM reference to study performances

Extension of the variational theory of complex rays to orthotropic shallow shell structures

International audienceNowadays, the interest of aerospace and automotive industries on virtual testing of medium-frequency vibrational behavior of shallow shell structures is growing. The development of software capable of predicting the vibrational response in such frequency range is still an open question because classical methods (i.e., FEM, SEA) are not fully suitable for the medium-frequency bandwidth. In this context the Variational Theory of Complex Rays (VTCR) is taking place as an ad-hoc technique to address medium-frequency problems. It is a Trefftz method based on a weak variational formulation. It allows great flexibility because any shape function that satisfies the governing equations can be used. This work further develops such theory. In particular, orthotropic materials are introduced in the VTCR formulation for shallow shell structures. A significant numerical example is proposed to show the strategy

Phosphorylation of RIPK1 serine 25 mediates IKK dependent control of extrinsic cell death in T cells

The Inhibitor of Kappa B Kinase (IKK) complex is a critical regulator of NF-kappa B activation. More recently, IKK has also been shown to repress RIPK1 dependent extrinsic cell death pathways by directly phosphorylating RIPK1 at serine 25. In T cells, IKK expression is essential for normal development in the thymus, by promoting survival of thymocytes independently of NF-kappa B activation. RIPK1 undergoes extensive phosphorylation following TNF stimulation in T cells, though which targets are required to repress RIPK1 has not been defined. Here, we show that TNF induced phosphorylation of RIPK1 at S25 is IKK dependent. We test the relevance of this phosphorylation event in T cells using mice with a RIPK1(S25D) phosphomimetic point mutation to endogenous RIPK1. We find that this mutation protects T cells from TNF induced cell death when IKK activity is inhibited in vitro, and can rescues development of IKK deficient thymocytes in vivo to a degree comparable with kinase dead RIPK1(D138N). Together, these data show that phosphorylation of RIPK1S25 by IKK represents a key regulatory event promoting survival of T cells by IKK

The Variational Theory of Complex Rays applied to the shallow shell theory

International audienceIn the last few decades the interest of aerospace and automotive industries towards the study of the medium-frequency response of complex shell structure frames has grown. Recently some dedicated ''wave'' computational approaches have been developed. Among them, a Trefftz technique called Variational Theory of Complex Rays (VTCR) is catching on as an ad hoc method to deal with such vibration problems. This work presents the development of the VTCR in the shallow shell theory to increase its effectiveness and flexibility. First, general theory is given and two key properties of the solution demonstrated. After that, two numerical examples are deeply analyzed

Survival of single positive thymocytes depends upon developmental control of RIPK1 kinase signaling by the IKK complex independent of NF-κB

NF-kappa B(nuclear factor kappa B) signaling is considered critical for single positive (SP) thymocyte development because loss of upstream activators of NF-kappa B, such as the IKK complex, arrests their development. We found that the compound ablation of RelA, cRel, and p50, required for canonical NF-kappa B transcription, had no impact upon thymocyte development. While IKK-deficient thymocytes were acutely sensitive to tumor necrosis factor (TNF)-induced cell death, Rel-deficient cells remained resistant, calling into question the importance of NF-kappa B as the IKK target required for thymocyte survival. Instead, we found that IKK controlled thymocyte survival by repressing cell-death-inducing activity of the serine/threonine kinase RIPK1. We observed that RIPK1 expression was induced during development of SP thymocytes and that IKK was required to prevent RIPK1-kinase-dependent death of SPs in vivo. Finally, we showed that IKK was required to protect Rel-deficient thymocytes from RIPK1-dependent cell death, underscoring the NF-kappa B-independent function of IKK during thymic development

Aspirin Extrusion From Human Platelets Through Multidrug Resistance Protein-4-Mediated Transport Evidence of a Reduced Drug Action in Patients After Coronary Artery Bypass Grafting

Objectives In this study we investigate: 1) the role of multidrug resistance protein-4 (MRP4), an organic anion unidirectional transporter, in modulating aspirin action on human platelet cyclooxygenase (COX)-1; and 2) whether the impairment of aspirin-COX-1 interaction, found in coronary artery bypass grafting (CABG) patients, could be dependent on MRP4-mediated transport. Background Platelets of CABG patients present a reduced sensitivity to aspirin despite in vivo and in vitro drug treatment. Aspirin is an organic anion and could be a substrate for MRP4. Methods Intracellular aspirin concentration and drug COX-1 activity, measured by thrombin-induced thromboxane B2 (TxB2) production, were evaluated in platelets obtained from healthy volunteers (HV) and hematopoietic-progenitor cell cultures reducing or not reducing MRP4-mediated transport. Platelet MRP4 expression was evaluated, in platelets from HV and CABG patients, by dot-blot or by immunogold-electromicrographs or immunofluorescence-microscopy analysis. Results Inhibition of MRP4-mediated transport by dipyridamole or Mk-571 increases aspirin entrapment and its in vitro effect on COX-1 activity (142.7 +/- 34.6 pg/10(8) cells vs. 343.7 +/- 169.3 pg/10(8) cells TxB2-production). Platelets derived from megakaryocytes transfected with MRP4 small interfering ribonucleic acid have a higher aspirin entrapment and drug COX-1 activity. Platelets from CABG patients showed a high expression of MRP4 whose in vitro inhibition enhanced aspirin effect on COX-1 (349 +/- 141 pg/10(8) cells vs. 1,670 +/- 646 pg/10(8) cells TxB2-production). Conclusions Aspirin is a substrate for MRP4 and can be extruded from platelet through its transportation. Aspirin effect on COX-1 is little-related to MRP4-mediated aspirin transport in HV, but in CABG patients with MRP4 over-expression, its pharmacological inhibition enhances aspirin action in an efficient way. (J Am Coll Cardiol 2011;58:752-61) (C) 2011 by the American College of Cardiology Foundatio