J. Exp. Med., Volume 188, Number 11, December 7, 1998 2067-2074

Stat5b Is Essential for Natural Killer Cell-mediated Proliferation and Cytolytic Activity

By Kazunori Imada,^* Eda T. Bloom, Hiroshi Nakajima,^* Judith A. Horvath-Arcidiacono, Garry B. Udy,^§ Helen W. Davey,^¶ and Warren J. Leonard^*

From the ^* Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1674; the  Division of Cell and Gene Therapy, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; the ^§ Ministry of Agriculture and Forestry (Verification Agency), Te Kuiti, New Zealand; and the ^¶ Dairy Science Group, AgResearch, Ruakura, Hamilton, New Zealand

We have analyzed the immune system in Stat5-deficient mice. Although Stat5a^/ splenocytes have a partial defect in anti-CD3-induced proliferation that can be overcome by high dose interleukin (IL)-2, we now demonstrate that defective proliferation in Stat5b^/ splenocytes cannot be corrected by this treatment. Interestingly, this finding may be at least partially explained by diminished expression of the IL-2 receptor  chain (IL-2R), which is a component of the receptors for both IL-2 and IL-15, although other defects may also exist. Similar to the defect in proliferation in activated splenocytes, freshly isolated splenocytes from Stat5b^/ mice exhibited greatly diminished proliferation in response to IL-2 and IL-15. This results from both a decrease in the number and responsiveness of natural killer (NK) cells. Corresponding to the diminished proliferation, basal as well as IL-2- and IL-15-mediated boosting of NK cytolytic activity was also greatly diminished. These data indicate an essential nonredundant role for Stat5b for potent NK cell-mediated proliferation and cytolytic activity.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Park, I.-K., Giovenzana, C., Hughes, T. L., Yu, J., Trotta, R., Caligiuri, M. A. (2009). The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development. Blood 113: 2470-2477 [Abstract] [Full Text]  
• Karpuzoglu, E., Phillips, R. A., Dai, R., Graniello, C., Gogal, R. M. Jr., Ahmed, S. A. (2009). Signal Transducer and Activation of Transcription (STAT) 4{beta}, a Shorter Isoform of Interleukin-12-Induced STAT4, Is Preferentially Activated by Estrogen. Endocrinology 150: 1310-1320 [Abstract] [Full Text]  
• Han, X, Ren, X, Jurickova, I, Groschwitz, K, Pasternak, B A, Xu, H, Wilson, T A, Hogan, S P, Denson, L A (2009). Regulation of intestinal barrier function by signal transducer and activator of transcription 5b. Gut 58: 49-58 [Abstract] [Full Text]  
• Rowley, J., Monie, A., Hung, C.-F., Wu, T.-C. (2008). Inhibition of Tumor Growth by NK1.1+ Cells and CD8+ T Cells Activated by IL-15 through Receptor {beta}/Common {gamma} Signaling in trans. J. Immunol. 181: 8237-8247 [Abstract] [Full Text]  
• Basham, B., Sathe, M., Grein, J., McClanahan, T., D'Andrea, A., Lees, E., Rascle, A. (2008). In vivo identification of novel STAT5 target genes. Nucleic Acids Res 36: 3802-3818 [Abstract] [Full Text]  
• Harb, J. G., Chyla, B. I., Huettner, C. S. (2008). Loss of Bcl-x in Ph+ B-ALL increases cellular proliferation and does not inhibit leukemogenesis. Blood 111: 3760-3769 [Abstract] [Full Text]  
• Hennighausen, L., Robinson, G. W. (2008). Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. Genes Dev. 22: 711-721 [Abstract] [Full Text]  
• de Totero, D., Meazza, R., Capaia, M., Fabbi, M., Azzarone, B., Balleari, E., Gobbi, M., Cutrona, G., Ferrarini, M., Ferrini, S. (2008). The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways. Blood 111: 517-524 [Abstract] [Full Text]  
• Chaudhry, U. I., Plitas, G., Burt, B. M., Kingham, T. P., Raab, J. R., DeMatteo, R. P. (2007). NK Dendritic Cells Expanded in IL-15 Exhibit Antitumor Responses In Vivo. J. Immunol. 179: 4654-4660 [Abstract] [Full Text]  
• Dai, X., Chen, Y., Di, L., Podd, A., Li, G., Bunting, K. D., Hennighausen, L., Wen, R., Wang, D. (2007). Stat5 Is Essential for Early B Cell Development but Not for B Cell Maturation and Function. J. Immunol. 179: 1068-1079 [Abstract] [Full Text]  
• Yao, Z., Kanno, Y., Kerenyi, M., Stephens, G., Durant, L., Watford, W. T., Laurence, A., Robinson, G. W., Shevach, E. M., Moriggl, R., Hennighausen, L., Wu, C., O'Shea, J. J. (2007). Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109: 4368-4375 [Abstract] [Full Text]  
• Zeng, R., Spolski, R., Casas, E., Zhu, W., Levy, D. E., Leonard, W. J. (2007). The molecular basis of IL-21-mediated proliferation. Blood 109: 4135-4142 [Abstract] [Full Text]  
• Chiossone, L., Vitale, C., Cottalasso, F., Moretti, S., Azzarone, B., Moretta, L., Mingari, M. C. (2007). Molecular analysis of the methylprednisolone-mediated inhibition of NK-cell function: evidence for different susceptibility of IL-2- versus IL-15-activated NK cells. Blood 109: 3767-3775 [Abstract] [Full Text]  
• Bernasconi, A., Marino, R., Ribas, A., Rossi, J., Ciaccio, M., Oleastro, M., Ornani, A., Paz, R., Rivarola, M. A., Zelazko, M., Belgorosky, A. (2006). Characterization of Immunodeficiency in a Patient With Growth Hormone Insensitivity Secondary to a Novel STAT5b Gene Mutation. Pediatrics 118: e1584-e1592 [Abstract] [Full Text]  
• Varker, K. A., Kondadasula, S. V., Go, M. R., Lesinski, G. B., Ghosh-Berkebile, R., Lehman, A., Monk, J. P., Olencki, T., Kendra, K., Carson, W. E. III (2006). Multiparametric Flow Cytometric Analysis of Signal Transducer and Activator of Transcription 5 Phosphorylation in Immune Cell Subsets In vitro and following Interleukin-2 Immunotherapy.. Clin. Cancer Res. 12: 5850-5858 [Abstract] [Full Text]  
• Cohen, A. C., Nadeau, K. C., Tu, W., Hwa, V., Dionis, K., Bezrodnik, L., Teper, A., Gaillard, M., Heinrich, J., Krensky, A. M., Rosenfeld, R. G., Lewis, D. B. (2006). Cutting Edge: Decreased Accumulation and Regulatory Function of CD4+CD25high T Cells in Human STAT5b Deficiency.. J. Immunol. 177: 2770-2774 [Abstract] [Full Text]  
• Taylor, D. K., Walsh, P. T., LaRosa, D. F., Zhang, J., Burchill, M. A., Farrar, M. A., Turka, L. A. (2006). Constitutive Activation of STAT5 Supersedes the Requirement for Cytokine and TCR Engagement of CD4+ T Cells in Steady-State Homeostasis. J. Immunol. 177: 2216-2223 [Abstract] [Full Text]  
• Lin, H., Nieda, M., Hutton, J. F., Rozenkov, V., Nicol, A. J. (2006). Comparative gene expression analysis of NKT cell subpopulations. J. Leukoc. Biol. 80: 164-173 [Abstract] [Full Text]  
• Fang, P., Kofoed, E. M., Little, B. M., Wang, X., Ross, R. J. M., Frank, S. J., Hwa, V., Rosenfeld, R. G. (2006). A Mutant Signal Transducer and Activator of Transcription 5b, Associated with Growth Hormone Insensitivity and Insulin-Like Growth Factor-I Deficiency, Cannot Function as a Signal Transducer or Transcription Factor. J. Clin. Endocrinol. Metab. 91: 1526-1534 [Abstract] [Full Text]  
• Yao, Z., Cui, Y., Watford, W. T., Bream, J. H., Yamaoka, K., Hissong, B. D., Li, D., Durum, S. K., Jiang, Q., Bhandoola, A., Hennighausen, L., O'Shea, J. J. (2006). Stat5a/b are essential for normal lymphoid development and differentiation. Proc. Natl. Acad. Sci. USA 103: 1000-1005 [Abstract] [Full Text]  
• Kovanen, P. E., Young, L., Al-Shami, A., Rovella, V., Pise-Masison, C. A., Radonovich, M. F., Powell, J., Fu, J., Brady, J. N., Munson, P. J., Leonard, W. J. (2005). Global analysis of IL-2 target genes: identification of chromosomal clusters of expressed genes. Int Immunol 17: 1009-1021 [Abstract] [Full Text]  
• Moucadel, V., Constantinescu, S. N. (2005). Differential STAT5 Signaling by Ligand-dependent and Constitutively Active Cytokine Receptors. J. Biol. Chem. 280: 13364-13373 [Abstract] [Full Text]  
• Takatori, H., Nakajima, H., Kagami, S.-i., Hirose, K., Suto, A., Suzuki, K., Kubo, M., Yoshimura, A., Saito, Y., Iwamoto, I. (2005). Stat5a Inhibits IL-12-Induced Th1 Cell Differentiation through the Induction of Suppressor of Cytokine Signaling 3 Expression. J. Immunol. 174: 4105-4112 [Abstract] [Full Text]  
• Takatori, H., Nakajima, H., Hirose, K., Kagami, S.-i., Tamachi, T., Suto, A., Suzuki, K., Saito, Y., Iwamoto, I. (2005). Indispensable Role of Stat5a in Stat6-Independent Th2 Cell Differentiation and Allergic Airway Inflammation. J. Immunol. 174: 3734-3740 [Abstract] [Full Text]  
• Sekine, Y., Yamamoto, T., Yumioka, T., Sugiyama, K., Tsuji, S., Oritani, K., Shimoda, K., Minoguchi, M., Yoshimura, A., Matsuda, T. (2005). Physical and Functional Interactions between STAP-2/BKS and STAT5. J. Biol. Chem. 280: 8188-8196 [Abstract] [Full Text]  
• Nelson, E. A., Walker, S. R., Alvarez, J. V., Frank, D. A. (2004). Isolation of Unique STAT5 Targets by Chromatin Immunoprecipitation-based Gene Identification. J. Biol. Chem. 279: 54724-54730 [Abstract] [Full Text]  
• Gonsky, R., Deem, R. L., Bream, J., Young, H. A., Targan, S. R. (2004). Enhancer Role of STAT5 in CD2 Activation of IFN-{gamma} Gene Expression. J. Immunol. 173: 6241-6247 [Abstract] [Full Text]  
• Kang, J., DiBenedetto, B., Narayan, K., Zhao, H., Der, S. D., Chambers, C. A. (2004). STAT5 Is Required for Thymopoiesis in a Development Stage-Specific Manner. J. Immunol. 173: 2307-2314 [Abstract] [Full Text]  
• Davoodi-Semiromi, A., Laloraya, M., Kumar, G. P., Purohit, S., Jha, R. K., She, J.-X. (2004). A Mutant Stat5b with Weaker DNA Binding Affinity Defines a Key Defective Pathway in Nonobese Diabetic Mice. J. Biol. Chem. 279: 11553-11561 [Abstract] [Full Text]  
• O'Sullivan, A., Chang, H.-C., Yu, Q., Kaplan, M. H. (2004). STAT4 Is Required for Interleukin-12-induced Chromatin Remodeling of the CD25 Locus. J. Biol. Chem. 279: 7339-7345 [Abstract] [Full Text]  
• Mitchell, T. J., Whittaker, S. J., John, S. (2003). Dysregulated Expression of COOH-Terminally Truncated Stat5 and Loss of IL2-Inducible Stat5-Dependent Gene Expression in Sezary Syndrome. Cancer Res. 63: 9048-9054 [Abstract] [Full Text]  
• Snow, J. W., Abraham, N., Ma, M. C., Herndier, B. G., Pastuszak, A. W., Goldsmith, M. A. (2003). Loss of Tolerance and Autoimmunity Affecting Multiple Organs in STAT5A/5B-Deficient Mice. J. Immunol. 171: 5042-5050 [Abstract] [Full Text]  
• Kofoed, E. M., Hwa, V., Little, B., Woods, K. A., Buckway, C. K., Tsubaki, J., Pratt, K. L., Bezrodnik, L., Jasper, H., Tepper, A., Heinrich, J. J., Rosenfeld, R. G. (2003). Growth Hormone Insensitivity Associated with a STAT5b Mutation. NEJM 349: 1139-1147 [Full Text]  
• Kelly, J. A., Spolski, R., Kovanen, P. E., Suzuki, T., Bollenbacher, J., Pise-Masison, C. A., Radonovich, M. F., Lee, S., Jenkins, N. A., Copeland, N. G., Morse, H. C. III, Leonard, W. J. (2003). Stat5 Synergizes with T Cell Receptor/Antigen Stimulation in the Development of Lymphoblastic Lymphoma. JEM 198: 79-89 [Abstract] [Full Text]  
• Waldburger, J.-M., Rossi, S., Hollander, G. A., Rodewald, H.-R., Reith, W., Acha-Orbea, H. (2003). Promoter IV of the class II transactivator gene is essential for positive selection of CD4+ T cells. Blood 101: 3550-3559 [Abstract] [Full Text]  
• Benekli, M., Baer, M. R., Baumann, H., Wetzler, M. (2003). Signal transducer and activator of transcription proteins in leukemias. Blood 101: 2940-2954 [Abstract] [Full Text]  
• Endo, T., Sasaki, A., Minoguchi, M., Joo, A., Yoshimura, A. (2003). CIS1 Interacts with the Y532 of the Prolactin Receptor and Suppresses Prolactin-Dependent STAT5 Activation. J Biochem 133: 109-113 [Abstract] [Full Text]  
• Kelly, J., Spolski, R., Imada, K., Bollenbacher, J., Lee, S., Leonard, W. J. (2003). A Role for Stat5 in CD8+ T Cell Homeostasis. J. Immunol. 170: 210-217 [Abstract] [Full Text]  
• Minagawa, M., Watanabe, H., Miyaji, C., Tomiyama, K., Shimura, H., Ito, A., Ito, M., Domen, J., Weissman, I. L., Kawai, K. (2002). Enforced Expression of Bcl-2 Restores the Number of NK Cells, But Does Not Rescue the Impaired Development of NKT Cells or Intraepithelial Lymphocytes, in IL-2/IL-15 Receptor {beta}-Chain-Deficient Mice. J. Immunol. 169: 4153-4160 [Abstract] [Full Text]  
• Nguyen, K. B., Salazar-Mather, T. P., Dalod, M. Y., Van Deusen, J. B., Wei, X.-q., Liew, F. Y., Caligiuri, M. A., Durbin, J. E., Biron, C. A. (2002). Coordinated and Distinct Roles for IFN-{alpha}{beta}, IL-12, and IL-15 Regulation of NK Cell Responses to Viral Infection. J. Immunol. 169: 4279-4287 [Abstract] [Full Text]  
• Ronn, S. G., Hansen, J. A., Lindberg, K., Karlsen, A. E., Billestrup, N. (2002). The Effect of Suppressor of Cytokine Signaling 3 on GH Signaling in {beta}-Cells. Mol. Endocrinol. 16: 2124-2134 [Abstract] [Full Text]  
• Shen, R., Kaplan, M. H. (2002). The Homeostasis But Not the Differentiation of T Cells Is Regulated by p27Kip1. J. Immunol. 169: 714-721 [Abstract] [Full Text]  
• Dong, S., Tweardy, D. J. (2002). Interactions of STAT5b-RARalpha , a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways. Blood 99: 2637-2646 [Abstract] [Full Text]  
• Snow, J. W., Abraham, N., Ma, M. C., Abbey, N. W., Herndier, B., Goldsmith, M. A. (2002). STAT5 promotes multilineage hematolymphoid development in vivo through effects on early hematopoietic progenitor cells. Blood 99: 95-101 [Abstract] [Full Text]  
• Horikawa, K., Kaku, H., Nakajima, H., Davey, H. W., Henninghausen, L., Iwamoto, I., Yasue, T., Kariyone, A., Takatsu, K. (2001). Essential Role of Stat5 for IL-5-Dependent IgH Switch Recombination in Mouse B Cells. J. Immunol. 167: 5018-5026 [Abstract] [Full Text]  
• Colucci, F., Samson, S. I., DeKoter, R. P., Lantz, O., Singh, H., Di Santo, J. P. (2001). Differential requirement for the transcription factor PU.1 in the generation of natural killer cells versus B and T cells. Blood 97: 2625-2632 [Abstract] [Full Text]  
• Kagami, S.-i., Nakajima, H., Suto, A., Hirose, K., Suzuki, K., Morita, S., Kato, I., Saito, Y., Kitamura, T., Iwamoto, I. (2001). Stat5a regulates T helper cell differentiation by several distinct mechanisms. Blood 97: 2358-2365 [Abstract] [Full Text]  
• Kazansky, A. V., Rosen, J. M. (2001). Signal Transducers and Activators of Transcription 5B Potentiates v-Src-mediated Transformation of NIH-3T3 Cells. Cell Growth Differ. 12: 1-7 [Abstract] [Full Text]  
• Friedrichsen, B. N., Galsgaard, E. D., Nielsen, J. H., Møldrup, A. (2001). Growth Hormone- and Prolactin-Induced Proliferation of Insulinoma Cells, INS-1, Depends on Activation of STAT5 (Signal Transducer and Activator of Transcription 5). Mol. Endocrinol. 15: 136-148 [Abstract] [Full Text]  
• Fehniger, T. A., Caligiuri, M. A. (2001). Interleukin 15: biology and relevance to human disease. Blood 97: 14-32 [Full Text]  
• Lee, C.-K., Rao, D. T., Gertner, R., Gimeno, R., Frey, A. B., Levy, D. E. (2000). Distinct Requirements for IFNs and STAT1 in NK Cell Function. J. Immunol. 165: 3571-3577 [Abstract] [Full Text]  
• Gollob, J. A., Veenstra, K. G., Jyonouchi, H., Kelly, A. M., Ferrieri, P., Panka, D. J., Altare, F., Fieschi, C., Casanova, J.-L., Frank, D. A., Mier, J. W. (2000). Impairment of STAT Activation by IL-12 in a Patient with Atypical Mycobacterial and Staphylococcal Infections. J. Immunol. 165: 4120-4126 [Abstract] [Full Text]  
• Zhang, S., Fukuda, S., Lee, Y., Hangoc, G., Cooper, S., Spolski, R., Leonard, W. J., Broxmeyer, H. E. (2000). Essential Role of Signal Transducer and Activator of Transcription (Stat)5a but Not Stat5b for Flt3-dependent Signaling. JEM 192: 719-728 [Abstract] [Full Text]  
• Lord, J. D., McIntosh, B. C., Greenberg, P. D., Nelson, B. H. (2000). The IL-2 Receptor Promotes Lymphocyte Proliferation and Induction of the c-myc, bcl-2, and bcl-x Genes Through the trans-Activation Domain of Stat5. J. Immunol. 164: 2533-2541 [Abstract] [Full Text]  
• Kagami, S.-i., Nakajima, H., Kumano, K., Suzuki, K., Suto, A., Imada, K., Davey, H. W., Saito, Y., Takatsu, K., Leonard, W. J., Iwamoto, I. (2000). Both Stat5a and Stat5b are required for antigen-induced eosinophil and T-cell recruitment into the tissue. Blood 95: 1370-1377 [Abstract] [Full Text]  
• Suzuki, K., Nakajima, H., Saito, Y., Saito, T., Leonard, W. J., Iwamoto, I. (2000). 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. Int Immunol 12: 123-132 [Abstract] [Full Text]  
• Yu, C.-L., Jin, Y.-J., Burakoff, S. J. (2000). Cytosolic Tyrosine Dephosphorylation of STAT5. POTENTIAL ROLE OF SHP-2 IN STAT5 REGULATION. J. Biol. Chem. 275: 599-604 [Abstract] [Full Text]  
• Soldaini, E., John, S., Moro, S., Bollenbacher, J., Schindler, U., Leonard, W. J. (2000). DNA Binding Site Selection of Dimeric and Tetrameric Stat5 Proteins Reveals a Large Repertoire of Divergent Tetrameric Stat5a Binding Sites. Mol. Cell. Biol. 20: 389-401 [Abstract] [Full Text]  
• Ward, A. C., Touw, I., Yoshimura, A. (2000). The Jak-Stat pathway in normal and perturbed hematopoiesis. Blood 95: 19-29 [Full Text]  
• Kaisho, T., Tsutsui, H., Tanaka, T., Tsujimura, T., Takeda, K., Kawai, T., Yoshida, N., Nakanishi, K., Akira, S. (1999). Impairment of Natural Killer Cytotoxic Activity and Interferon {gamma} Production in CCAAT/Enhancer Binding Protein {gamma}-deficient Mice. JEM 190: 1573-1582 [Abstract] [Full Text]  
• Zhang, J., Scordi, I., Smyth, M. J., Lichtenheld, M. G. (1999). Interleukin 2 Receptor Signaling Regulates the Perforin Gene through Signal Transducer and Activator of Transcription (Stat)5 Activation of Two Enhancers. JEM 190: 1297-1308 [Abstract] [Full Text]  
• Matsumoto, A., Seki, Y., Kubo, M., Ohtsuka, S., Suzuki, A., Hayashi, I., Tsuji, K., Nakahata, T., Okabe, M., Yamada, S., Yoshimura, A. (1999). Suppression of STAT5 Functions in Liver, Mammary Glands, and T Cells in Cytokine-Inducible SH2-Containing Protein 1 Transgenic Mice. Mol. Cell. Biol. 19: 6396-6407 [Abstract] [Full Text]  
• Akira, S. (1999). Functional Roles of STAT Family Proteins: Lessons from Knockout Mice. Stem Cells 17: 138-146 [Abstract] [Full Text]  
• John, S., Vinkemeier, U., Soldaini, E., Darnell, J. E. Jr., Leonard, W. J. (1999). The Significance of Tetramerization in Promoter Recruitment by Stat5. Mol. Cell. Biol. 19: 1910-1918 [Abstract] [Full Text]  
• LEONARD, W.J., IMADA, K., NAKAJIMA, H., PUEL, A., SOLDAINI, E., JOHN, S. (1999). Signaling via the IL-2 and IL-7 Receptors from the Membrane to the Nucleus. Cold Spring Harb Symp Quant Biol 64: 417-424 [Abstract]  
• Kulms, D., Schwarz, T. (2001). Ultraviolet Radiation Inhibits Interleukin-2-induced Tyrosine Phosphorylation and the Activation of STAT5 in T Lymphocytes. J. Biol. Chem. 276: 12849-12855 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS