Journal of Experimental Medicine, Vol 184, 325-336, Copyright © 1996 by Rockefeller University Press

ARTICLES

Differential effects of interleukin-15 and interleukin-2 on differentiation of bipotential T/natural killer progenitor cells

G Leclercq, V Debacker, M de Smedt and J Plum
Department of Clinical Chemistry, Microbiology and Immunology, University of Ghent, University Hospital, Belgium.

Bipotential T/natural killer (NK) progenitor cells are destined to differentiate mainly into T cell receptor (TCR) alpha beta and TCR gamma delta cells in a thymic microenvironment, whereas extrathymically they selectively develop into NK cells. The exact environmental conditions that are required for differentiation into these three leukocyte populations are largely unknown. In this report, we have investigated and compared the effect of interleukin (IL)-15 and IL-2 in this process. The IL-15 receptor is composed of the gamma and beta chains of the IL-2 receptor (IL-2R gamma and IL-2R beta) and of a specific alpha chain (IL-15R alpha). Here, it is shown that IL-15 mRNA is mainly expressed in thymic epithelial stromal cells, whereas IL-2 mRNA is exclusively expressed in thymocytes. IL-2R beta-expressing cells were present in the fetal thymus with a CD25-CD44+Fc gamma R+HSA- /low TCR- phenotype, which is characteristic of progenitor cells. These cells also expressed IL-15R alpha messenger RNA. Sorted IL-2R beta + TCR- cells differentiated into TCR alpha beta and TCR gamma delta cells after transfer to alymphoid thymic lobes, whereas culture of the same sorted cells in cell suspension in the presence of IL-15 resulted in the generation of functional NK cells. This shows that IL-2R beta +TCR- cells of the fetal thymus contain bipotential T/NK progenitors. Addition of low concentrations of IL-15 to fetal thymic organ culture (FTOC) resulted in an increase of all T cell subpopulations. The largest expansion occurred in the TCR gamma delta compartment. In contrast, low concentrations of IL-2 did not result in a higher total cell number and did not induce outgrowth of TCR gamma delta cells. High concentrations of IL-15 blocked TCR alpha beta development and shifted differentiation towards NK cells. Differentiation towards TCR gamma delta cells still proceeded. High concentrations of IL-2 similarly induced development into NK cells, but the cell number was fourfold lower than in IL-15 cultures. Importantly, blocking of IL-2R alpha in IL-2-treated FTOC resulted in a drastic increase in cell number, indicating that IL-2R alpha negatively regulates cell expansion. Collectively, these experiments provide direct evidence that IL-15 and IL-2 differentially affect the differentiation of bipotential T/NK progenitors.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Lai, Y.-G., Hou, M.-S., Hsu, Y.-W., Chang, C.-L., Liou, Y.-H., Tsai, M.-H., Lee, F., Liao, N.-S. (2008). IL-15 Does Not Affect IEL Development in the Thymus but Regulates Homeostasis of Putative Precursors and Mature CD8{alpha}{alpha}+ IELs in the Intestine. J. Immunol. 180: 3757-3765 [Abstract] [Full Text]  
• Fujimoto, S., Ikawa, T., Kina, T., Yokota, Y. (2007). Forced expression of Id2 in fetal thymic T cell progenitors allows some of their progeny to adopt NK cell fate. Int Immunol 19: 1175-1182 [Abstract] [Full Text]  
• Malarkannan, S., Regunathan, J., Chu, H., Kutlesa, S., Chen, Y., Zeng, H., Wen, R., Wang, D. (2007). Bcl10 Plays a Divergent Role in NK Cell-Mediated Cytotoxicity and Cytokine Generation. J. Immunol. 179: 3752-3762 [Abstract] [Full Text]  
• Di Sabatino, A, Ciccocioppo, R, Cupelli, F, Cinque, B, Millimaggi, D, Clarkson, M M, Paulli, M, Cifone, M G, Corazza, G R (2006). Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease. Gut 55: 469-477 [Abstract] [Full Text]  
• Sun, A., Wei, H., Sun, R., Xiao, W., Yang, Y., Tian, Z. (2006). Human Interleukin-15 Improves Engraftment of Human T Cells in NOD-SCID Mice. CVI 13: 227-234 [Abstract] [Full Text]  
• Lin, C.-W., Liu, T.-Y., Chen, S.-U., Wang, K.-T., Medeiros, L. J., Hsu, S.-M. (2005). CD94 1A transcripts characterize lymphoblastic lymphoma/leukemia of immature natural killer cell origin with distinct clinical features. Blood 106: 3567-3574 [Abstract] [Full Text]  
• Garcia-Ojeda, M. E., Dejbakhsh-Jones, S., Chatterjea-Matthes, D., Mukhopadhyay, A., BitMansour, A., Weissman, I. L., Brown, J. M. Y., Strober, S. (2005). Stepwise Development of Committed Progenitors in the Bone Marrow That Generate Functional T Cells in the Absence of the Thymus. J. Immunol. 175: 4363-4373 [Abstract] [Full Text]  
• Stevenaert, F., Van Beneden, K., De Colvenaer, V., Franki, A. S., Debacker, V., Boterberg, T., Deforce, D., Pfeffer, K., Plum, J., Elewaut, D., Leclercq, G. (2005). Ly49 and CD94/NKG2 receptor acquisition by NK cells does not require lymphotoxin-{beta} receptor expression. Blood 106: 956-962 [Abstract] [Full Text]  
• Vodyanik, M. A., Bork, J. A., Thomson, J. A., Slukvin, I. I. (2005). Human embryonic stem cell-derived CD34+ cells: efficient production in the coculture with OP9 stromal cells and analysis of lymphohematopoietic potential. Blood 105: 617-626 [Abstract] [Full Text]  
• Alpdogan, O., Eng, J. M., Muriglan, S. J., Willis, L. M., Hubbard, V. M., Tjoe, K. H., Terwey, T. H., Kochman, A., van den Brink, M. R. M. (2005). Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation. Blood 105: 865-873 [Abstract] [Full Text]  
• Toomey, J. A., Gays, F., Foster, D., Brooks, C. G. (2003). Cytokine requirements for the growth and development of mouse NK cells in vitro. J. Leukoc. Biol. 74: 233-242 [Abstract] [Full Text]  
• Koka, R., Burkett, P. R., Chien, M., Chai, S., Chan, F., Lodolce, J. P., Boone, D. L., Ma, A. (2003). Interleukin (IL)-15R{alpha}-deficient Natural Killer Cells Survive in Normal but Not IL-15R{alpha}-deficient Mice. J. Exp. Med. 197: 977-984 [Abstract] [Full Text]  
• Schotte, R., Rissoan, M.-C., Bendriss-Vermare, N., Bridon, J.-M., Duhen, T., Weijer, K., Briere, F., Spits, H. (2003). The transcription factor Spi-B is expressed in plasmacytoid DC precursors and inhibits T-, B-, and NK-cell development. Blood 101: 1015-1023 [Abstract] [Full Text]  
• Gurney, K. B., Yang, O. O., Wilson, S. B., Uittenbogaart, C. H. (2002). TCR{gamma}{delta}+ and CD161+ Thymocytes Express HIV-1 in the SCID-hu Mouse, Potentially Contributing to Immune Dysfunction in HIV Infection. J. Immunol. 169: 5338-5346 [Abstract] [Full Text]  
• De Creus, A., Van Beneden, K., Stevenaert, F., Debacker, V., Plum, J., Leclercq, G. (2002). Developmental and Functional Defects of Thymic and Epidermal V{gamma}3 Cells in IL-15-Deficient and IFN Regulatory Factor-1-Deficient Mice. J. Immunol. 168: 6486-6493 [Abstract] [Full Text]  
• Mariner, J. M., Mamane, Y., Hiscott, J., Waldmann, T. A., Azimi, N. (2002). IFN Regulatory Factor 4 Participates in the Human T Cell Lymphotropic Virus Type I-Mediated Activation of the IL-15 Receptor {alpha} Promoter. J. Immunol. 168: 5667-5674 [Abstract] [Full Text]  
• Loza, M. J., Zamai, L., Azzoni, L., Rosati, E., Perussia, B. (2002). Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells. Blood 99: 1273-1281 [Abstract] [Full Text]  
• Alonso-C., L. M., Munoz, J. J., Zapata, A. G. (2001). Delineation of Intrathymic T, NK, and Dendritic Cell (DC) Progenitors in Fetal and Adult Rats: Demonstration of a Bipotent T/DC Intermediate Precursor. J. Immunol. 167: 3635-3641 [Abstract] [Full Text]  
• Ikawa, T., Fujimoto, S., Kawamoto, H., Katsura, Y., Yokota, Y. (2001). Commitment to natural killer cells requires the helix-loop-helix inhibitor Id2. Proc. Natl. Acad. Sci. USA 10.1073/pnas.091537598v1 [Abstract] [Full Text]  
• Le, P. T., Adams, K. L., Zaya, N., Mathews, H. L., Storkus, W. J., Ellis, T. M. (2001). Human Thymic Epithelial Cells Inhibit IL-15- and IL-2-Driven Differentiation of NK Cells from the Early Human Thymic Progenitors. J. Immunol. 166: 2194-2201 [Abstract] [Full Text]  
• Fehniger, T. A., Caligiuri, M. A. (2001). Interleukin 15: biology and relevance to human disease. Blood 97: 14-32 [Full Text]  
• Verma, S., Hiby, S. E., Loke, Y. W., King, A. (2000). Human Decidual Natural Killer Cells Express the Receptor for and Respond to the Cytokine Interleukin 15. Biol. Reprod. 62: 959-968 [Abstract] [Full Text]  
• Ma, A., Boone, D. L., Lodolce, J. P. (2000). The Pleiotropic Functions of Interleukin 15: Not So Interleukin 2-like After All. J. Exp. Med. 191: 753-756 [Full Text]  
• Ikawa, T., Kawamoto, H., Fujimoto, S., Katsura, Y. (1999). Commitment of Common T/Natural Killer (NK) Progenitors to Unipotent T and NK Progenitors in the Murine Fetal Thymus Revealed by a Single Progenitor Assay. J. Exp. Med. 190: 1617-1626 [Abstract] [Full Text]  
• Azimi, N., Jacobson, S., Leist, T., Waldmann, T. A. (1999). Involvement of IL-15 in the Pathogenesis of Human T Lymphotropic Virus Type I-Associated Myelopathy/Tropical Spastic Paraparesis: Implications for Therapy with a Monoclonal Antibody Directed to the IL-2/15R{beta} Receptor. J. Immunol. 163: 4064-4072 [Abstract] [Full Text]  
• Josien, R., Wong, B. R., Li, H.-L., Steinman, R. M., Choi, Y. (1999). TRANCE, a TNF Family Member, Is Differentially Expressed on T Cell Subsets and Induces Cytokine Production in Dendritic Cells. J. Immunol. 162: 2562-2568 [Abstract] [Full Text]  
• Plum, J., De Smedt, M., Verhasselt, B., Offner, F., Kerre, T., Vanhecke, D., Leclercq, G., Vandekerckhove, B. (1999). In Vitro Intrathymic Differentiation Kinetics of Human Fetal Liver CD34+CD38- Progenitors Reveals a Phenotypically Defined Dendritic/T-NK Precursor Split. J. Immunol. 162: 60-68 [Abstract] [Full Text]  
• Imada, K., Bloom, E. T., Nakajima, H., Horvath-Arcidiacono, J. A., Udy, G. B., Davey, H. W., Leonard, W. J. (1998). Stat5b Is Essential for Natural Killer Cell-mediated Proliferation and Cytolytic Activity. J. Exp. Med. 188: 2067-2074 [Abstract] [Full Text]  
• Hacein-Bey, S., Basile, G. D. S., Lemerle, J., Fischer, A., Cavazzana-Calvo, M. (1998). gamma c Gene Transfer in the Presence of Stem Cell Factor, FLT-3L, Interleukin-7 (IL-7), IL-1alpha , and IL-15 Cytokines Restores T-Cell Differentiation From gamma c(-) X-Linked Severe Combined Immunodeficiency Hematopoietic Progenitor Cells in Murine Fetal Thymic Organ Cultures. Blood 92: 4090-4097 [Abstract] [Full Text]  
• Durum, S. K., Lee, C.-K., Geiman, T. M., Murphy, W. J., Muegge, K. (1998). CD16 Cross-Linking Blocks Rearrangement of the TCR{beta} Locus and Development of {alpha}{beta} T Cells and Induces Development of NK Cells from Thymic Progenitors. J. Immunol. 161: 3325-3329 [Abstract] [Full Text]  
• Shaw, S. G., Maung, A. A., Steptoe, R. J., Thomson, A. W., Vujanovic3, N. L. (1998). Expansion of Functional NK Cells in Multiple Tissue Compartments of Mice Treated with Flt3-Ligand: Implications for Anti-Cancer and Anti-Viral Therapy. J. Immunol. 161: 2817-2824 [Abstract] [Full Text]  
• Dooms, H., Desmedt, M., Vancaeneghem, S., Rottiers, P., Goossens, V., Fiers, W., Grooten, J. (1998). Quiescence-Inducing and Antiapoptotic Activities of IL-15 Enhance Secondary CD4+ T Cell Responsiveness to Antigen. J. Immunol. 161: 2141-2150 [Abstract] [Full Text]  
• Wang, H., Diamond, R. A., Rothenberg, E. V. (1998). Cross-lineage expression of Ig-beta (B29) in thymocytes: Positive and negative gene regulation to establish T cell identity. Proc. Natl. Acad. Sci. USA 95: 6831-6836 [Abstract] [Full Text]  
• Yamada, Y., Sugawara, K., Hata, T., Tsuruta, K., Moriuchi, R., Maeda, T., Atogami, S., Murata, K., Fujimoto, K., Kohno, T., Tsukasaki, K., Tomonaga, M., Hirakata, Y.-i., Kamihira, S. (1998). Interleukin-15 (IL-15) Can Replace the IL-2 Signal in IL-2-Dependent Adult T-Cell Leukemia (ATL) Cell Lines: Expression of IL-15 Receptor alpha  on ATL Cells. Blood 91: 4265-4272 [Abstract] [Full Text]  
• Azimi, N., Brown, K., Bamford, R. N., Tagaya, Y., Siebenlist, U., Waldmann, T. A. (1998). Human T cell lymphotropic virus type I Tax protein trans-activates interleukin 15 gene transcription through an NF-kappa B site. Proc. Natl. Acad. Sci. USA 95: 2452-2457 [Abstract] [Full Text]  
• Voss, S. D., Daley, J., Ritz, J., Robertson, M. J. (1998). Participation of the CD94 Receptor Complex in Costimulation of Human Natural Killer Cells. J. Immunol. 160: 1618-1626 [Abstract] [Full Text]  
• Mitnacht, R., Bischof, A., Torres-Nagel, N., Hunig, T. (1998). Opposite CD4/CD8 Lineage Decisions of CD4+8+ Mouse and Rat Thymocytes to Equivalent Triggering Signals: Correlation with Thymic Expression of a Truncated CD8{alpha} Chain in Mice But Not Rats. J. Immunol. 160: 700-707 [Abstract] [Full Text]  
• Carlyle, J. R., Michie, A. M., Cho, S. K., Zuniga-Pflucker, J. C. (1998). Natural Killer Cell Development and Function Precede {alpha}{beta} T Cell Differentiation in Mouse Fetal Thymic Ontogeny. J. Immunol. 160: 744-753 [Abstract] [Full Text]  
• Williams, N. S., Moore, T. A., Schatzle, J. D., Puzanov, I. J., Sivakumar, P.V., Zlotnik, A., Bennett, M., Kumar, V. (1997). Generation of Lytic Natural Killer 1.1+, Ly-49- Cells from Multipotential Murine Bone Marrow Progenitors in a Stroma-free Culture: Definition of Cytokine Requirements and Developmental Intermediates. J. Exp. Med. 186: 1609-1614 [Abstract] [Full Text]  
• Carlyle, J. R., Michie, A. M., Furlonger, C., Nakano, T., Lenardo, M. J., Paige, C. J., Zuniga-Pflucker, J. C. (1997). Identification of a Novel Developmental Stage Marking Lineage Commitment of Progenitor Thymocytes. J. Exp. Med. 186: 173-182 [Abstract] [Full Text]  
• Boesteanu, A., Silva, A. D. D., Nakajima, H., Leonard, W. J., Peschon, J. J., Joyce, S. (1997). Distinct Roles for Signals Relayed through the Common Cytokine Receptor gamma  Chain and Interleukin 7 Receptor alpha  Chain in Natural T Cell Development. J. Exp. Med. 186: 331-336 [Abstract] [Full Text]  
• Aiba, Y., Hirayama, F., Ogawa, M. (1997). Clonal Proliferation and Cytokine Requirement of Murine Progenitors for Natural Killer Cells. Blood 89: 4005-4012 [Abstract] [Full Text]  
• Suzuki, H., Duncan, G. S., Takimoto, H., Mak, T. W. (1997). Abnormal Development of Intestinal Intraepithelial Lymphocytes and Peripheral Natural Killer Cells in Mice Lacking the IL-2 Receptor beta  Chain. J. Exp. Med. 185: 499-506 [Abstract] [Full Text]  
• Ikawa, T., Fujimoto, S., Kawamoto, H., Katsura, Y., Yokota, Y. (2001). Commitment to natural killer cells requires the helix-loop-helix inhibitor Id2. Proc. Natl. Acad. Sci. USA 98: 5164-5169 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS