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Science 3 November 1995:
Vol. 270. no. 5237, pp. 800 - 802
DOI: 10.1126/science.270.5237.800
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Reports

Defective Lymphoid Development in Mice Lacking Jak3

Tetsuya Nosaka,  Jan M. A. van Deursen,  Ralph A. Tripp,  William E. Thierfelder,  Bruce A. Witthuhn,  Anthony P. McMickle,  Peter C. Doherty,  Gerard C. Grosveld,  James N. Ihle (1)

The Janus tyrosine kinases (Jaks) play a central role in signaling through cytokine receptors. Although Jak1, Jak2, and Tyk2 are widely expressed, Jak3 is predominantly expressed in hematopoietic cells and is known to associate only with the common ((c)) chain of the interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15 receptors. Homozygous mutant mice in which the Jak3 gene had been disrupted were generated by gene targeting. Jak3-deficient mice had profound reductions in thymocytes and severe B cell and T cell lymphopenia similar to severe combined immunodeficiency disease (SCID), and the residual T cells and B cells were functionally deficient. Thus, Jak3 plays a critical role in (c) signaling and lymphoid development.


T. Nosaka, W. E. Thierfelder, B. A. Witthuhn, J. N. Ihle, Department of Biochemistry, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
J. M. A. van Deursen and G. C. Grosveld, Department of Genetics, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
R. A. Tripp, A. P. McMickle, P. C. Doherty, Department of Immunology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
(1) To whom correspondence should be addressed.


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   Abstract »    Full Text »    PDF »
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Blood 97, 2269-2277
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NF-{{kappa}}B/Rel Participation in the Lymphokine-Dependent Proliferation of T Lymphoid Cells.
A. L. Mora, J. Youn, A. D. Keegan, and M. Boothby (2001)
J. Immunol. 166, 2218-2227
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Blood 97, 14-32
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U. Mei{beta}ner, H. Blum, M. Schnare, M. Rollinghoff, and A. Gessner (2001)
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Lack of Phosphotyrosine Phosphatase SHP-1 Expression in Malignant T-Cell Lymphoma Cells Results from Methylation of the SHP-1 Promoter.
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S. Tsujino, J. P. Di Santo, A. Takaoka, T. L. McKernan, S. Noguchi, C. Taya, H. Yonekawa, T. Saito, T. Taniguchi, and H. Fujii (2000)
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Fates of human B-cell precursors.
T. W. LeBien (2000)
Blood 96, 9-23
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Hierarchy of Protein Tyrosine Kinases in Interleukin-2 (IL-2) Signaling: Activation of Syk Depends on Jak3; However, Neither Syk nor Lck Is Required for IL-2-Mediated STAT Activation.
Y.-J. Zhou, K. S. Magnuson, T. P. Cheng, M. Gadina, D. M. Frucht, J. Galon, F. Candotti, R. L. Geahlen, P. S. Changelian, and J. J. O'Shea (2000)
Mol. Cell. Biol. 20, 4371-4380
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Interleukin (IL)-7 Induces Rapid Activation of Pyk2, Which Is Bound to Janus Kinase 1 and IL-7Ralpha.
N. Benbernou, K. Muegge, and S. K. Durum (2000)
J. Biol. Chem. 275, 7060-7065
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Murine Pro-B Cells Require IL-7 and Its Receptor Complex to Up-Regulate IL-7R{alpha}, Terminal Deoxynucleotidyltransferase, and c{micro} Expression.
C. Wei, R. Zeff, and I. Goldschneider (2000)
J. Immunol. 164, 1961-1970
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Activation of p38 Mitogen-Activated Protein Kinase In Vivo Selectively Induces Apoptosis of CD8+ but Not CD4+ T Cells.
C. Merritt, H. Enslen, N. Diehl, D. Conze, R. J. Davis, and M. Rincón (2000)
Mol. Cell. Biol. 20, 936-946
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Complex Effects of Naturally Occurring Mutations in the JAK3 Pseudokinase Domain: Evidence for Interactions between the Kinase and Pseudokinase Domains.
M. Chen, A. Cheng, F. Candotti, Y.-J. Zhou, A. Hymel, A. Fasth, L. D. Notarangelo, and J. J. O'Shea (2000)
Mol. Cell. Biol. 20, 947-956
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Janus kinase 3 (Jak3) is essential for common cytokine receptor {gamma} chain ({gamma}c)-dependent signaling: comparative analysis of {gamma}c, Jak3, and {gamma}c and Jak3 double-deficient mice.
K. Suzuki, H. Nakajima, Y. Saito, T. Saito, W. J. Leonard, and I. Iwamoto (2000)
Int. Immunol. 12, 123-132
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The Jak-Stat pathway in normal and perturbed hematopoiesis.
A. C. Ward, I. Touw, and A. Yoshimura (2000)
Blood 95, 19-29
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Impairment of Natural Killer Cytotoxic Activity and Interferon {gamma} Production in CCAAT/Enhancer Binding Protein {gamma}-deficient Mice.
T. Kaisho, H. Tsutsui, T. Tanaka, T. Tsujimura, K. Takeda, T. Kawai, N. Yoshida, K. Nakanishi, and S. Akira (1999)
J. Exp. Med. 190, 1573-1582
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Differential Regulation of Constitutive Major Histocompatibility Complex Class I Expression in T and B Lymphocytes.
C.-K. Lee, R. Gimeno, and D. E. Levy (1999)
J. Exp. Med. 190, 1451-1464
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The Jak Family Tyrosine Kinase Jak3 Is Required for IL-2 Synthesis by Naive/Resting CD4+ T Cells.
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J. Biol. Chem. 274, 31531-31542
   Abstract »    Full Text »    PDF »
Gene Duplication of Zebrafish JAK2 Homologs Is Accompanied by Divergent Embryonic Expression Patterns: Only jak2a Is Expressed During Erythropoiesis.
A. C. Oates, A. Brownlie, S. J. Pratt, D. V. Irvine, E. C. Liao, B. H. Paw, K. J. Dorian, S. L. Johnson, J. H. Postlethwait, L. I. Zon, et al. (1999)
Blood 94, 2622-2636
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Defective Development of {gamma}/{delta} T Cells in Interleukin 7 Receptor–deficient Mice Is Due to Impaired Expression of T Cell Receptor {gamma} Genes.
J. Kang, M. Coles, and D. H. Raulet (1999)
J. Exp. Med. 190, 973-982
   Abstract »    Full Text »    PDF »
Targeting Janus Kinase 3 in Mast Cells Prevents Immediate Hypersensitivity Reactions and Anaphylaxis.
R. Malaviya, D. Zhu, I. Dibirdik, and F. M. Uckun (1999)
J. Biol. Chem. 274, 27028-27038
   Abstract »    Full Text »    PDF »
Reconstitution of Early Lymphoid Proliferation and Immune Function in Jak3-Deficient Mice by Interleukin-3.
M. P. Brown, T. Nosaka, R. A. Tripp, J. Brooks, J. M.A. van Deursen, M. K. Brenner, P. C. Doherty, and J. N. Ihle (1999)
Blood 94, 1906-1914
   Abstract »    Full Text »    PDF »
IL-10 Transgenic Mice Present a Defect in T Cell Development Reminiscent to SCID Patients.
M. Rouleau, F. Cottrez, M. Bigler, S. Antonenko, J. M. Carballido, A. Zlotnik, M.-G. Roncarolo, and H. Groux (1999)
J. Immunol. 163, 1420-1427
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Dysregulated Myelopoiesis in Mice Lacking Jak3.
W. J. Grossman, J. W. Verbsky, L. Yang, L. J. Berg, L. E. Fields, D. D. Chaplin, and L. Ratner (1999)
Blood 94, 932-939
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Fusion of the ets Transcription Factor TEL to Jak2 Results in Constitutive Jak-Stat Signaling.
J. M.-Y. Ho, B. K. Beattie, J. A. Squire, D. A. Frank, and D. L. Barber (1999)
Blood 93, 4354-4364
   Abstract »    Full Text »    PDF »
Genetic Dissection of Sle Pathogenesis: Sle3 on Murine Chromosome 7 Impacts T Cell Activation, Differentiation, and Cell Death.
C. Mohan, Y. Yu, L. Morel, P. Yang, and E. K. Wakeland (1999)
J. Immunol. 162, 6492-6502
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IL-7 receptor {alpha}+ CD3– cells in the embryonic intestine induces the organizing center of Peyer's patches.
H. Yoshida, K. Honda, R. Shinkura, S. Adachi, S. Nishikawa, K. Maki, K. Ikuta, and S.-I. Nishikawa (1999)
Int. Immunol. 11, 643-655
   Abstract »    Full Text »    PDF »
Functional Roles of STAT Family Proteins: Lessons from Knockout Mice.
S. Akira (1999)
Stem Cells 17, 138-146
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Downregulation of JAK3 Protein Levels in T Lymphocytes by Prostaglandin E2 and Other Cyclic Adenosine Monophosphate-Elevating Agents: Impact on Interleukin-2 Receptor Signaling Pathway.
V. Kolenko, P. Rayman, B. Roy, M. K. Cathcart, J. O'Shea, R. Tubbs, L. Rybicki, R. Bukowski, and J. Finke (1999)
Blood 93, 2308-2318
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Role of Interleukin (IL)-2 Receptor beta -Chain Subdomains and Shc in p38 Mitogen-activated Protein (MAP) Kinase and p54 MAP Kinase (Stress-activated Protein Kinase/c-Jun N-terminal Kinase) Activation. IL-2-DRIVEN PROLIFERATION IS INDEPENDENT OF p38 AND p54 MAP KINASE ACTIVATION.
A. E. Hunt, F. V. Lali, J. D. Lord, B. H. Nelson, T. Miyazaki, K. J. Tracey, and B. M. J. Foxwell (1999)
J. Biol. Chem. 274, 7591-7597
   Abstract »    Full Text »    PDF »
IL-4 Selectively Inhibits IL-2-Triggered Stat5 Activation, But Not Proliferation, in Human T Cells.
A. Castro, T. K. Sengupta, D. C. Ruiz, E. Yang, and L. B. Ivashkiv (1999)
J. Immunol. 162, 1261-1269
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Distinct Effects of Jak3 Signaling on {alpha}{beta} and {gamma}{delta} Thymocyte Development.
E. E. Eynon, F. Livak, K. Kuida, D. G. Schatz, and R. A. Flavell (1999)
J. Immunol. 162, 1448-1459
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Thymic Stromal Lymphopoietin: A Cytokine That Promotes the Development of IgM+ B Cells In Vitro and Signals Via a Novel Mechanism.
S. D. Levin, R. M. Koelling, S. L. Friend, D. E. Isaksen, S. F. Ziegler, R. M. Perlmutter, and A. G. Farr (1999)
J. Immunol. 162, 677-683
   Abstract »    Full Text »    PDF »
Virus-specific immunity after gene therapy in a murine model of severe combined immunodeficiency.
K. D. Bunting, K. J. Flynn, J. M. Riberdy, P. C. Doherty, and B. P. Sorrentino (1999)
PNAS 96, 232-237
   Abstract »    Full Text »    PDF »
Differential Roles of Cytokine Signaling during T-cell Development.
R. MORIGGL, J.-C. MARINE, D.J. TOPHAM, S. TEGLUND, V. SEXL, C. MCKAY, R. PIEKORZ, D. WANG, E. PARGANAS, A. YOSHIMURA, et al. (1999)
Cold Spring Harb Symp Quant Biol 64, 389-396
   Abstract »    PDF »


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