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Warren J Leonard - One of the best experts on this subject based on the ideXlab platform.
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the common Cytokine Receptor γ chain family of Cytokines
Cold Spring Harbor Perspectives in Biology, 2018Co-Authors: Jianxin Lin, Warren J LeonardAbstract:Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of Cytokines based on their sharing the common Cytokine Receptor γ chain (γc), which was originally discovered as the third Receptor component of the IL-2 Receptor, IL-2Rγ. The IL2RG gene is located on the X chromosome and is mutated in humans with X-linked severe combined immunodeficiency (XSCID). The breadth of the defects in XSCID could not be explained solely by defects in IL-2 signaling, and it is now clear that γc is a shared Receptor component of the six Cytokines noted above, making XSCID a disease of defective Cytokine signaling. Janus kinase (JAK)3 associates with γc, and JAK3-deficient SCID phenocopies XSCID, findings that served to stimulate the development of JAK3 inhibitors as immunosuppressants. γc family Cytokines collectively control broad aspects of lymphocyte development, growth, differentiation, and survival, and these Cytokines are clinically important, related to allergic and autoimmune diseases and cancer as well as immunodeficiency. In this review, we discuss the actions of these Cytokines, their critical biological roles and signaling pathways, focusing mainly on JAK/STAT (signal transducers and activators of transcription) signaling, and how this information is now being used in clinical therapeutic efforts.
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new insights into the regulation of t cells by gamma c family Cytokines
Nature Reviews Immunology, 2009Co-Authors: Yrina Rochman, Rosanne Spolski, Warren J LeonardAbstract:In this Review, the authors discuss the central roles of the common Cytokine Receptor γ-chain (γc) family of Cytokines, as well as the related Cytokine TSLP, in the homeostasis, proliferation and differentiation of various T cell subsets and describe how these Cytokines could be exploited for therapeutic purposes.
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interleukin 21 a Cytokine Cytokine Receptor system that has come of age
Journal of Leukocyte Biology, 2008Co-Authors: Warren J Leonard, Rong Zeng, Rosanne SpolskiAbstract:Interleukin-21 (IL-21) and its Receptor represent the sixth Cytokine system whose actions were recognized to require the common Cytokine Receptor gamma chain. IL-21 is produced by activated CD4+ T cells, natural killer T cells, and follicular T helper cells and has actions on a range of lymphohematopoietic lineages. Among its many effects, IL-21 serves a critical role for immunoglobulin production and terminal B cell differentiation, acts as a T cell comitogen and can drive the expansion of CD8+ T cells, can negatively regulate dendritic cell function and plays an essential role in the differentiation of Th17 cells. Importantly, IL-21 is implicated in the pathogenesis of autoimmunity and exhibits potent actions as an antitumor agent. The ability to regulate and manipulate the actions of IL-21, therefore, has important implications for immunoregulation and the therapy of human disease.
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cloning of a type i Cytokine Receptor most related to the il 2 Receptor β chain
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Katsutoshi Ozaki, Kristine Kikly, David Michalovich, Peter R Young, Warren J LeonardAbstract:We have identified a type I Cytokine Receptor, which we have termed novel interleukin Receptor (NILR), that is most related to the IL-2 Receptor β chain (IL-2Rβ) and physically adjacent to the IL-4 Receptor α chain gene on chromosome 16. NILR mRNA is most highly expressed in thymus and spleen, and is induced by phytohemagglutinin in human peripheral blood mononuclear cells. NILR protein was detected on human T cell lymphotropic virus type I-transformed T cell lines, Raji B cells, and YT natural killer-like cells. Artificial homodimerization of the NILR cytoplasmic domain confers proliferation to Ba/F3 murine pro-B cells but not to 32D myeloid progenitor cells or CTLL-2 murine helper T cells. In these latter cells, heterodimerization of IL-2Rβ and the common Cytokine Receptor γ chain (γc) cytoplasmic domains allows potent proliferation, whereas such heterodimerization of NILR with γc does not. This finding suggests that NILR has signaling potential but that a full understanding of its signaling partner(s) is not yet clear. Like IL-2Rβ, NILR associates with Jak1 and mediates Stat5 activation.
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role of bcl 2 in alpha beta t cell development in mice deficient in the common Cytokine Receptor gamma chain the requirement for bcl 2 differs depending on the tcr mhc affinity
Journal of Immunology, 1999Co-Authors: Hiroshi Nakajima, Warren J LeonardAbstract:Mice lacking the common Cytokine Receptor γ-chain (γc) exhibit severely compromised T cell development, with diminished Bcl-2 expression in mature (CD4+ or CD8+) thymocytes and peripheral T cells. Enforced expression of Bcl-2 in these mice partially rescued αβ T cell development but not γδ T cell development. Transgenic expression of the OVA-specific DO11.10 (DO10) TCR also could modestly increase thymocyte numbers, and T cells expressing the transgenic TCR (KJ1-26+ T cells) were found in the periphery. Interestingly, the presence of KJ1-26+ T cells was dependent on the MHC background and was seen in the moderate affinity H-2d/d background but not in the higher affinity H-2d/b background in γc-deficient mice. In contrast, KJ1-26+ T cells exist in the periphery in both the H-2d/d and H-2d/b backgrounds in DO10 transgenic γc wild-type mice. These results suggest that the importance of γc-dependent signals for T cell development differs depending on the affinity of TCR for MHC. Moreover, enforced expression of Bcl-2 had a much greater effect on the development of γc-deficient T cells expressing the DO10 TCR in the high affinity H-2d/b background than in the H-2d/d background, suggesting that γc-dependent Bcl-2 expression influences T cell development in a TCR/MHC-dependent manner.
Tadamitsu Kishimoto - One of the best experts on this subject based on the ideXlab platform.
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gp130 and the interleukin 6 family of Cytokines
Annual Review of Immunology, 1997Co-Authors: Tetsuya Taga, Tadamitsu KishimotoAbstract:▪ Abstract Receptors for most interleukins and Cytokines that regulate immune and hematopoietic systems belong to the class I Cytokine Receptor family. These molecules form multichain Receptor complexes in order to exhibit high-affinity binding to, and mediate biological functions of, their respective Cytokines. In most cases, these functional Receptor complexes share common signal transducing Receptor components that are also in the class I Cytokine Receptor family, i.e. gp130, common β, and common γ molecules. Interleukin-6 and related Cytokines, interleukin-11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1 are all pleiotropic and exhibit overlapping biological functions. Functional Receptor complexes for this interleukin-6 family of Cytokines share gp130 as a component critical for signal transduction. Unlike Cytokines sharing common β and common γ chains that mainly function in hematopoietic and lymphoid cell systems, the interleukin-6 family of Cytokines f...
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critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the Cytokine Receptor family
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: Masaaki Murakami, Tetsuya Taga, Masashi Narazaki, Masahiko Hibi, Hideo Yawata, Kiyoshi Yasukawa, Michinari Hamaguchi, Tadamitsu KishimotoAbstract:Interleukin 6 (IL-6) signal is transduced through gp130 that associates with a complex of IL-6 and IL-6 Receptor. Truncations or amino acid substitutions offe introduced in the cytoplasmic region of human gp130, and the mutant cDNAs were transfected into murine interleukin 3-dependent cells to determine amino acid residues critical for generating the IL-6-mediated growth signal. In the 277-amino acid cytoplasmic region of gp130, a 61-amino acid region proximal to the transmembrane domain was sufficient for generating the growth signal. In this region, two short segments were significantly homologous with other Cytokine-Receptor family members. One segment is conserved in almost all members of the family, and the other is found especially in granulocyte colony-stimulating factor Receptor, interleukin 2 Receptor beta chain, erythropoietin Receptor, KH97 (a granulocyte/macrophage colony-stimulating factor Receptor-associated molecule), and interleukin 3 Receptor. gp130 molecules with mutations in either of these two segments could not transduce growth signal. Loss of signal-transducing ability of gp130 with such a mutation coincided with disappearance of IL-6-induced tyrosine phosphorylation of gp130.
James N Ihle - One of the best experts on this subject based on the ideXlab platform.
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Cytokine Receptor signalling
Nature, 1995Co-Authors: James N IhleAbstract:Many cell functions are regulated by members of the Cytokine Receptor superfamily. Signalling by these Receptors depends upon their association with Janus kinases (JAKs), which couple ligand binding to tyrosine phosphorylation of signalling proteins recruited to the Receptor complex. Among these are the signal transducers and activators of transcription (STATs), a family of transcription factors that contribute to the diversity of Cytokine responses.
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Jaks and Stats in signaling by the Cytokine Receptor superfamily
Trends in Genetics, 1995Co-Authors: James N Ihle, Ian M. KerrAbstract:Abstract Many Cytokines mediate their biological effects through interaction with a distinct family of Receptors termed the Cytokine Receptor superfamily. Although members of this family lack catalytic domains, they couple ligand binding to tyrosine phosphorylation. Recent studies have shown that a novel family of cytoplasmic protein tyrosine kinases, termed the Janus kinases (Jaks), associate with the Cytokine Receptors and are catalytically activated after ligand binding. The activated Jaks phosphorylate and activate members of a novel family of transcription factors termed signal transducers and activators of transcription (Stats). In addition, many Cytokines induce the phosphorylation of SHC, Vav and the p85 subunit of PI-3 kinase. The region of the Receptors proximal to the cytoplasmic membrane is required for Jak association, mitogenesis, Stat activation and Vav phosphorylation. The membrane-distal region, which contains the major sites of tyrosine phosphorylation, it required for phosphorylation of SHC and p85, not for mitogenesis, thus allowing functional dissection of the signaling pathways activated by Cytokines.
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signaling through the hematopoietic Cytokine Receptors
Annual Review of Immunology, 1995Co-Authors: James N Ihle, Bruce A. Witthuhn, Frederick W. Quelle, Koh Yamamoto, Olli SilvennoinenAbstract:Hematopoiesis is regulated through the interaction of a variety of growth factors with specific Receptors of the Cytokine Receptor superfamily. Although lacking catalytic domain s, all the Receptors couple ligand
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signaling through the hematopoietic Cytokine Receptors
Annual Review of Immunology, 1995Co-Authors: James N Ihle, Bruce A. Witthuhn, Frederick W. Quelle, Koh Yamamoto, Olli SilvennoinenAbstract:Hematopoiesis is regulated through the interaction of a variety of growth factors with specific Receptors of the Cytokine Receptor superfamily. Although lacking catalytic domains, all the Receptors couple ligand binding to the rapid induction of protein tyrosine phosphorylation. This is mediated through a novel family of protein tyrosine kinases termed the Janus kinases (Jaks) which associate with the Receptors and are activated following ligand binding. Depending upon the Cytokine/Receptor system, one or more of the four known Jaks (Jak1, Jak2, Jak3, Tyk2) is/are involved. The activated Jaks phosphorylate both themselves and the Receptor subunits, creating docking sites for SH2-containing proteins including SHC, which couples Receptor engagement to activation of the ras pathway, and HCP, a protein tyrosine phosphatase which negatively affects the response. In addition, the Jaks phosphorylate one or more of a family of signal transducers and activators of transcription (Stats). Phosphorylation of Stats induces their nuclear translocation and DNA-binding activity. Activation of Stats is independent of activation of the ras pathway and represents a novel signaling pathway correlated with mitogenesis.
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Signaling by the Cytokine Receptor superfamily: JAKs and STATs
Trends in Biochemical Sciences, 1994Co-Authors: James N Ihle, Bruce A. Witthuhn, Frederick W. Quelle, Koh Yamamoto, William E. Thierfelder, Kreider Bl, Olli SilvennoinenAbstract:Abstract A variety of Cytokines, lymphokines and growth factors functionsby interacting with Receptors that are members of the Cytokine Receptor superfamily. These Receptors share extracellular motifs and have limited similarity in their cytoplasmic domains. Although lacking catalytic domains, this family of Receptors couples ligand binding with the induction of tyrosine phosphorylation. Recent studies have shown that this is mediated by members of the Janus kinase (JAK) family of cytoplasmic protein tyrosine kinases. JAKs physically associate with the membrane-proximal region of the ligand-bound-Receptor, leading to their tyrosine phosphorylation and activation. The activated JAKs phosphorylate the Receptors as well as cytoplasmic proteins belonging to a family of transcription factors called the signal transducers and activators of transcription (STATs), providing a novel signaling pathway that is shared by all members of the Cytokine Receptor superfamily.
Olli Silvennoinen - One of the best experts on this subject based on the ideXlab platform.
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signaling through the hematopoietic Cytokine Receptors
Annual Review of Immunology, 1995Co-Authors: James N Ihle, Bruce A. Witthuhn, Frederick W. Quelle, Koh Yamamoto, Olli SilvennoinenAbstract:Hematopoiesis is regulated through the interaction of a variety of growth factors with specific Receptors of the Cytokine Receptor superfamily. Although lacking catalytic domain s, all the Receptors couple ligand
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signaling through the hematopoietic Cytokine Receptors
Annual Review of Immunology, 1995Co-Authors: James N Ihle, Bruce A. Witthuhn, Frederick W. Quelle, Koh Yamamoto, Olli SilvennoinenAbstract:Hematopoiesis is regulated through the interaction of a variety of growth factors with specific Receptors of the Cytokine Receptor superfamily. Although lacking catalytic domains, all the Receptors couple ligand binding to the rapid induction of protein tyrosine phosphorylation. This is mediated through a novel family of protein tyrosine kinases termed the Janus kinases (Jaks) which associate with the Receptors and are activated following ligand binding. Depending upon the Cytokine/Receptor system, one or more of the four known Jaks (Jak1, Jak2, Jak3, Tyk2) is/are involved. The activated Jaks phosphorylate both themselves and the Receptor subunits, creating docking sites for SH2-containing proteins including SHC, which couples Receptor engagement to activation of the ras pathway, and HCP, a protein tyrosine phosphatase which negatively affects the response. In addition, the Jaks phosphorylate one or more of a family of signal transducers and activators of transcription (Stats). Phosphorylation of Stats induces their nuclear translocation and DNA-binding activity. Activation of Stats is independent of activation of the ras pathway and represents a novel signaling pathway correlated with mitogenesis.
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Signaling by the Cytokine Receptor superfamily: JAKs and STATs
Trends in Biochemical Sciences, 1994Co-Authors: James N Ihle, Bruce A. Witthuhn, Frederick W. Quelle, Koh Yamamoto, William E. Thierfelder, Kreider Bl, Olli SilvennoinenAbstract:Abstract A variety of Cytokines, lymphokines and growth factors functionsby interacting with Receptors that are members of the Cytokine Receptor superfamily. These Receptors share extracellular motifs and have limited similarity in their cytoplasmic domains. Although lacking catalytic domains, this family of Receptors couples ligand binding with the induction of tyrosine phosphorylation. Recent studies have shown that this is mediated by members of the Janus kinase (JAK) family of cytoplasmic protein tyrosine kinases. JAKs physically associate with the membrane-proximal region of the ligand-bound-Receptor, leading to their tyrosine phosphorylation and activation. The activated JAKs phosphorylate the Receptors as well as cytoplasmic proteins belonging to a family of transcription factors called the signal transducers and activators of transcription (STATs), providing a novel signaling pathway that is shared by all members of the Cytokine Receptor superfamily.
Stacy Schlutsmeyer - One of the best experts on this subject based on the ideXlab platform.
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il 28 il 29 and their class ii Cytokine Receptor il 28r
Nature Immunology, 2003Co-Authors: Paul O Sheppard, Wayne R Kindsvogel, Stacy Schlutsmeyer, Katherine E Henderson, Theodore E Whitmore, Rolf E Kuestner, Ursula Garrigues, Carl W Birks, Jenny Roraback, Craig D OstranderAbstract:Cytokines play a critical role in modulating the innate and adaptive immune systems. Here, we have identified from the human genomic sequence a family of three Cytokines, designated interleukin 28A (IL-28A), IL-28B and IL-29, that are distantly related to type I interferons (IFNs) and the IL-10 family. We found that like type I IFNs, IL-28 and IL-29 were induced by viral infection and showed antiviral activity. However, IL-28 and IL-29 interacted with a heterodimeric class II Cytokine Receptor that consisted of IL-10 Receptor beta (IL-10Rbeta) and an orphan class II Receptor chain, designated IL-28Ralpha. This newly described Cytokine family may serve as an alternative to type I IFNs in providing immunity to viral infection.
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a soluble class ii Cytokine Receptor il 22ra2 is a naturally occurring il 22 antagonist
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Scott R Presnell, Julia Parrishnovak, Wayne R Kindsvogel, Steve Jaspers, Zhi Chen, Stacey R Dillon, Zeren Gao, Teresa Gilbert, Karen Madden, Stacy SchlutsmeyerAbstract:Abstract IL-22 is an IL-10 homologue that binds to and signals through the class II Cytokine Receptor heterodimer IL-22RA1/CRF2–4. IL-22 is produced by T cells and induces the production of acute-phase reactants in vitro and in vivo, suggesting its involvement in inflammation. Here we report the identification of a class II Cytokine Receptor designated IL-22RA2 (IL-22 Receptor-α 2) that appears to be a naturally expressed soluble Receptor. IL-22RA2 shares amino acid sequence homology with IL-22RA1 (also known as IL-22R, zcytor11, and CRF2–9) and is physically adjacent to IL-20Rα and IFN-γR1 on chromosome 6q23.3–24.2. We demonstrate that IL-22RA2 binds specifically to IL-22 and neutralizes IL-22-induced proliferation of BaF3 cells expressing IL-22 Receptor subunits. IL-22RA2 mRNA is highly expressed in placenta and spleen by Northern blotting. PCR analysis using RNA from various tissues and cell lines showed that IL-22RA2 was expressed in a range of tissues, including those in the digestive, female reproductive, and immune systems. In situ hybridization revealed the dominant cell types expressing IL-22RA2 were mononuclear cells and epithelium. Because IL-22 induces the expression of acute phase reactants, IL-22RA2 may play an important role as an IL-22 antagonist in the regulation of inflammatory responses.
