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Science 3 November 1995:
Vol. 270. no. 5237, pp. 794 - 797
DOI: 10.1126/science.270.5237.794
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Reports

Defects in B Lymphocyte Maturation and T Lymphocyte Activation in Mice Lacking Jak3

Daniel C. Thomis,  Christine B. Gurniak,  Elizabeth Tivol,  Arlene H. Sharpe,  Leslie J. Berg (1)

Biochemical studies of signaling mediated by many cytokine and growth factor receptors have implicated members of the Jak family of tyrosine kinases in these pathways. Specifically, Jak3 has been shown to be associated with the interleukin-2 (IL-2) receptor chain, a component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Mice lacking Jak3 showed a severe block in B cell development at the pre-B stage in the bone marrow. In contrast, although the thymuses of these mice were small, T cell maturation progressed relatively normally. In response to mitogenic signals, peripheral T cells in Jak3-deficient mice did not proliferate and secreted small amounts of IL-2. These data demonstrate that Jak3 is critical for the progression of B cell development in the bone marrow and for the functional competence of mature T cells.


D. C. Thomis, C. B. Gurniak, L. J. Berg, Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.
E. Tivol and A. H. Sharpe, Departments of Pathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA.
(1) To whom correspondence should be addressed.


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PNAS
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Fates of human B-cell precursors.
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J. D. Alvarez, D. H. Yasui, H. Niida, T. Joh, D. Y. Loh, and T. Kohwi-Shigematsu (2000)
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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)
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T. Kaisho, H. Tsutsui, T. Tanaka, T. Tsujimura, K. Takeda, T. Kawai, N. Yoshida, K. Nakanishi, and S. Akira (1999)
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J. Kang, M. Coles, and D. H. Raulet (1999)
J. Exp. Med. 190, 973-982
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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
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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
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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
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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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L. Li, Y. Xia, A. Nguyen, Y. H. Lai, L. Feng, T. R. Mosmann, and D. Lo (1999)
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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
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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
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Signaling via the IL-2 and IL-7 Receptors from the Membrane to the Nucleus.
W.J. LEONARD, K. IMADA, H. NAKAJIMA, A. PUEL, E. SOLDAINI, and S. JOHN (1999)
Cold Spring Harb Symp Quant Biol 64, 417-424
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Interleukin 7 Receptor Control of  T Cell Receptor gamma  Gene Rearrangement: Role of Receptor-associated Chains and Locus Accessibility.
S. K. Durum, S. Candeias, H. Nakajima, W. J. Leonard, A. M. Baird, L. J. Berg, and K. Muegge (1998)
J. Exp. Med. 188, 2233-2241
   Abstract »    Full Text »    PDF »
Stat5b Is Essential for Natural Killer Cell-mediated Proliferation and Cytolytic Activity.
K. Imada, E. T. Bloom, H. Nakajima, J. A. Horvath-Arcidiacono, G. B. Udy, H. W. Davey, and W. J. Leonard (1998)
J. Exp. Med. 188, 2067-2074
   Abstract »    Full Text »    PDF »
The IL-2 Receptor Promotes Proliferation, bcl-2 and bcl-x Induction, But Not Cell Viability Through the Adapter Molecule Shc.
J. D. Lord, B. C. McIntosh, P. D. Greenberg, and B. H. Nelson (1998)
J. Immunol. 161, 4627-4633
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Role of JAK3 in CD40-Mediated Signaling.
H. H. Jabara, R. H. Buckley, J. L. Roberts, G. Lefranc, J. Loiselet, G. Khalil, and R. S. Geha (1998)
Blood 92, 2435-2440
   Abstract »    Full Text »    PDF »
Characterization of a Mobile Stat6 Activation Motif in the Human IL-4 Receptor.
J. J. Ryan, L. J. McReynolds, H. Huang, K. Nelms, and W. E. Paul (1998)
J. Immunol. 161, 1811-1821
   Abstract »    Full Text »    PDF »
Role of Tyrosine Kinases in Induction of the c-jun Proto-oncogene in Irradiated B-lineage Lymphoid Cells.
P. A. Goodman, L. B. Niehoff, and F. M. Uckun (1998)
J. Biol. Chem. 273, 17742-17748
   Abstract »    Full Text »    PDF »
Impaired Interleukin 4 Signaling in T Helper Type 1 Cells.
H. Huang and W. E. Paul (1998)
J. Exp. Med. 187, 1305-1313
   Abstract »    Full Text »    PDF »
Cytokine-induced survival of activated T cells in vitro and in vivo.
A. T. Vella, S. Dow, T. A. Potter, J. Kappler, and P. Marrack (1998)
PNAS 95, 3810-3815
   Abstract »    Full Text »    PDF »
Signal Transduction Pathways Regulating Hematopoietic Differentiation.
T. E. Smithgall (1998)
Pharmacol. Rev. 50, 1-20
   Abstract »    Full Text »    PDF »
Requirement for Jak3 in Mature T Cells: Its Role in Regulation of T Cell Homeostasis.
S. J. Sohn, K. A. Forbush, N. Nguyen, B. Witthuhn, T. Nosaka, J. N. Ihle, and R. M. Perlmutter (1998)
J. Immunol. 160, 2130-2138
   Abstract »    Full Text »    PDF »
Development of Autologous, Oligoclonal, Poorly Functioning T Lymphocytes in a Patient With Autosomal Recessive Severe Combined Immunodeficiency Caused by Defects of the Jak3 Tyrosine Kinase.
D. Brugnoni, L. D. Notarangelo, A. Sottini, P. Airo, M. Pennacchio, E. Mazzolari, S. Signorini, F. Candotti, A. Villa, P. Mella, et al. (1998)
Blood 91, 949-955
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Impairment of  T and B Cell Development by Treatment with a Type I Interferon.
Q. Lin, C. Dong, and M. D. Cooper (1998)
J. Exp. Med. 187, 79-87
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Distinct tyrosine phosphorylation sites in JAK3 kinase domain positively and negatively regulate its enzymatic activity.
Y.-J. Zhou, E. P. Hanson, Y.-Q. Chen, K. Magnuson, M. Chen, P. G. Swann, R. L. Wange, P. S. Changelian, and J. J. O'Shea (1997)
PNAS 94, 13850-13855
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Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins.
S. Takemoto, J. C. Mulloy, A. Cereseto, T.-S. Migone, B. K. R. Patel, M. Matsuoka, K. Yamaguchi, K. Takatsuki, S. Kamihira, J. D. White, et al. (1997)
PNAS 94, 13897-13902
   Abstract »    Full Text »    PDF »
Structural and Functional Basis for JAK3-Deficient Severe Combined Immunodeficiency.
F. Candotti, S. A. Oakes, J. A. Johnston, S. Giliani, R. F. Schumacher, P. Mella, M. Fiorini, A. G. Ugazio, R. Badolato, L. D. Notarangelo, et al. (1997)
Blood 90, 3996-4003
   Abstract »    Full Text »    PDF »
Jak1 Plays an Essential Role for Receptor Phosphorylation and Stat Activation in Response to Granulocyte Colony-Stimulating Factor.
K. Shimoda, J. Feng, H. Murakami, S. Nagata, D. Watling, N. C. Rogers, G. R. Stark, I. M. Kerr, and J. N. Ihle (1997)
Blood 90, 597-604
   Abstract »    Full Text »    PDF »


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