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Warren J. Leonard

Bio: Warren J. Leonard is an academic researcher from National Institutes of Health. The author has contributed to research in topics: T cell & Receptor. The author has an hindex of 117, co-authored 384 publications receiving 52747 citations. Previous affiliations of Warren J. Leonard include Stanford University & University of South Florida.


Papers
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Journal ArticleDOI
TL;DR: IL-6 orchestrates a series of 'downstream' cytokine-dependent signaling pathways that, in concert with TGF-β, amplify RORγt-dependent differentiation of TH-17 cells.
Abstract: T helper cells that produce interleukin 17 (IL-17; 'T(H)-17 cells') are a distinct subset of proinflammatory cells whose in vivo function requires IL-23 but whose in vitro differentiation requires only IL-6 and transforming growth factor-beta (TGF-beta). We demonstrate here that IL-6 induced expression of IL-21 that amplified an autocrine loop to induce more IL-21 and IL-23 receptor in naive CD4(+) T cells. Both IL-21 and IL-23, along with TGF-beta, induced IL-17 expression independently of IL-6. The effects of IL-6 and IL-21 depended on STAT3, a transcription factor required for the differentiation of T(H)-17 cells in vivo. IL-21 and IL-23 induced the orphan nuclear receptor RORgammat, which in synergy with STAT3 promoted IL-17 expression. IL-6 therefore orchestrates a series of 'downstream' cytokine-dependent signaling pathways that, in concert with TGF-beta, amplify RORgammat-dependent differentiation of T(H)-17 cells.

2,046 citations

Journal ArticleDOI
TL;DR: The Jak-STAT pathway is the focus of this chapter, a novel mechanism in which cytosolic latent transcription factors, known as signal transducers and activators of transcription (STATs), are tyrosine phosphorylated by Janus family tyrosin kinases (Jaks), allowing STAT protein dimerization and nuclear translocation.
Abstract: Cytokines and interferons are molecules that play central roles in the regulation of a wide array of cellular functions in the lympho-hematopoietic system. These factors stimulate proliferation, differentiation, and survival signals, as well as specialized functions in host resistance to pathogens. Although cytokines are known to activate multiple signaling pathways that together mediate these important functions, one of these pathways, the Jak-STAT pathway, is the focus of this chapter. This pathway is triggered by both cytokines and interferons, and it very rapidly allows the transduction of an extracellular signal into the nucleus. The pathway uses a novel mechanism in which cytosolic latent transcription factors, known as signal transducers and activators of transcription (STATs), are tyrosine phosphorylated by Janus family tyrosine kinases (Jaks), allowing STAT protein dimerization and nuclear translocation. STATs then can modulate the expression of target genes. The basic biology of this system, including the range of known Jaks and STATs, is discussed, as are the defects in animals and humans lacking some of these signaling molecules.

1,749 citations

Journal ArticleDOI
09 Apr 1993-Cell
TL;DR: In this article, the IL-2R gamma gene and the locus for X-linked severe combined immunodeficiency (XSCID) appear to be at the same position.

1,254 citations

Journal ArticleDOI
17 Dec 1993-Science
TL;DR: Given its role in more than one cytokine receptor system, the common gamma chain (gamma c) is proposed as the designation for IL-2R gamma, which was shown to be physically associated with the IL-7 receptor by using chemical cross-linking.
Abstract: The interleukin-2 receptor gamma chain (IL-2R gamma) is a necessary component of functional IL-2 receptors. IL-2R gamma mutations result in X-linked severe combined immunodeficiency (XSCID) in humans, a disease characterized by the presence of few or no T cells. In contrast, SCID patients with IL-2 deficiency and IL-2-deficient mice have normal numbers of T cells, suggesting that IL-2R gamma is part of more than one cytokine receptor. By using chemical cross-linking, IL-2R gamma was shown to be physically associated with the IL-7 receptor. The presence of IL-2R gamma augmented both IL-7 binding affinity and the efficiency of internalization of IL-7. These findings may help explain the defects of XSCID. Given its role in more than one cytokine receptor system, the common gamma chain (gamma c) is proposed as the designation for IL-2R gamma.

1,133 citations

Journal ArticleDOI
01 Mar 1995-Immunity
TL;DR: Differences in humans and mice lacking gamma c expression indicate species-specific differences in the roles of gamma c-dependent cytokines or in the existence of redundant pathways.

1,030 citations


Cited by
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Journal ArticleDOI
TL;DR: There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.
Abstract: At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

9,131 citations

Journal ArticleDOI
TL;DR: A comprehensive review of spatiotemporal pattern formation in systems driven away from equilibrium is presented in this article, with emphasis on comparisons between theory and quantitative experiments, and a classification of patterns in terms of the characteristic wave vector q 0 and frequency ω 0 of the instability.
Abstract: A comprehensive review of spatiotemporal pattern formation in systems driven away from equilibrium is presented, with emphasis on comparisons between theory and quantitative experiments. Examples include patterns in hydrodynamic systems such as thermal convection in pure fluids and binary mixtures, Taylor-Couette flow, parametric-wave instabilities, as well as patterns in solidification fronts, nonlinear optics, oscillatory chemical reactions and excitable biological media. The theoretical starting point is usually a set of deterministic equations of motion, typically in the form of nonlinear partial differential equations. These are sometimes supplemented by stochastic terms representing thermal or instrumental noise, but for macroscopic systems and carefully designed experiments the stochastic forces are often negligible. An aim of theory is to describe solutions of the deterministic equations that are likely to be reached starting from typical initial conditions and to persist at long times. A unified description is developed, based on the linear instabilities of a homogeneous state, which leads naturally to a classification of patterns in terms of the characteristic wave vector q0 and frequency ω0 of the instability. Type Is systems (ω0=0, q0≠0) are stationary in time and periodic in space; type IIIo systems (ω0≠0, q0=0) are periodic in time and uniform in space; and type Io systems (ω0≠0, q0≠0) are periodic in both space and time. Near a continuous (or supercritical) instability, the dynamics may be accurately described via "amplitude equations," whose form is universal for each type of instability. The specifics of each system enter only through the nonuniversal coefficients. Far from the instability threshold a different universal description known as the "phase equation" may be derived, but it is restricted to slow distortions of an ideal pattern. For many systems appropriate starting equations are either not known or too complicated to analyze conveniently. It is thus useful to introduce phenomenological order-parameter models, which lead to the correct amplitude equations near threshold, and which may be solved analytically or numerically in the nonlinear regime away from the instability. The above theoretical methods are useful in analyzing "real pattern effects" such as the influence of external boundaries, or the formation and dynamics of defects in ideal structures. An important element in nonequilibrium systems is the appearance of deterministic chaos. A greal deal is known about systems with a small number of degrees of freedom displaying "temporal chaos," where the structure of the phase space can be analyzed in detail. For spatially extended systems with many degrees of freedom, on the other hand, one is dealing with spatiotemporal chaos and appropriate methods of analysis need to be developed. In addition to the general features of nonequilibrium pattern formation discussed above, detailed reviews of theoretical and experimental work on many specific systems are presented. These include Rayleigh-Benard convection in a pure fluid, convection in binary-fluid mixtures, electrohydrodynamic convection in nematic liquid crystals, Taylor-Couette flow between rotating cylinders, parametric surface waves, patterns in certain open flow systems, oscillatory chemical reactions, static and dynamic patterns in biological media, crystallization fronts, and patterns in nonlinear optics. A concluding section summarizes what has and has not been accomplished, and attempts to assess the prospects for the future.

6,145 citations

Journal ArticleDOI
10 Jun 1976-Nature
TL;DR: This is an interpretive review of first-order difference equations, which can exhibit a surprising array of dynamical behaviour, from stable points, to a bifurcating hierarchy of stable cycles, to apparently random fluctuations.
Abstract: First-order difference equations arise in many contexts in the biological, economic and social sciences. Such equations, even though simple and deterministic, can exhibit a surprising array of dynamical behaviour, from stable points, to a bifurcating hierarchy of stable cycles, to apparently random fluctuations. There are consequently many fascinating problems, some concerned with delicate mathematical aspects of the fine structure of the trajectories, and some concerned with the practical implications and applications. This is an interpretive review of them.

6,118 citations

Journal ArticleDOI
TL;DR: The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases.
Abstract: ▪ Abstract The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-κB is through interactions with an inhibitor protein called IκB. Recent evidence confirms the existence of multiple forms of IκB that appear to regulate NF-κB by distinct mechanisms. NF-κB can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-κB to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of IκB. Exciting new research has elaborated several important and unexpected findings that...

5,833 citations

Journal ArticleDOI
TL;DR: Recently, significant advances have been made in elucidating the details of the pathways through which signals are transmitted to the NF-kappa B:I kappa B complex in the cytosol and their implications for the study of NF-Kappa B.
Abstract: ▪ Abstract The transcription factor NF-κB, more than a decade after its discovery, remains an exciting and active area of study. The involvement of NF-κB in the expression of numerous cytokines and adhesion molecules has supported its role as an evolutionarily conserved coordinating element in the organism's response to situations of infection, stress, and injury. Recently, significant advances have been made in elucidating the details of the pathways through which signals are transmitted to the NF-κB:IκB complex in the cytosol. The field now awaits the discovery and characterization of the kinase responsible for the inducible phosphorylation of IκB proteins. Another exciting development has been the demonstration that in certain situations NF-κB acts as an anti-apoptotic protein; therefore, elucidation of the mechanism by which NF-κB protects against cell death is an important goal. Finally, the generation of knockouts of members of the NF-κB/IκB family has allowed the study of the roles of these protein...

5,324 citations