Control of CD4 effector fate: transforming growth factor beta 1 and interleukin 2 synergize to prevent apoptosis and promote effector expansion

doi:10.1084/jem.182.3.699

This Article

	Full Text (PDF, 1471K)
	Alert me when this article is cited
	Citation Map

Services

	Email this article
	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new content in the JEM
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via CrossRef
	Citing Articles via Google Scholar

Google Scholar

	Articles by Zhang, X.
	Articles by Swain, S. L.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Zhang, X.
	Articles by Swain, S. L.


Social Bookmarking

	What's this?

ARTICLES

Control of CD4 effector fate: transforming growth factor beta 1 and interleukin 2 synergize to prevent apoptosis and promote effector expansion

X Zhang, L Giangreco, HE Broome, CM Dargan and SL Swain
Department of Biology, University of California, San Diego, La Jolla 92093-0063, USA.

The signals that determine the size and duration of the primary T cell immune response are not well defined. We studied CD4 T cells at an important checkpoint in their development: when they have become effectors and are ready to rapidly mediate effector functions, both via direct interaction with antigen (Ag)-presenting cells and via cytokine production. We determined the effects of specific Ag and the cytokines interleukin (IL) 2 and transforming growth factor (TGF) beta 1 on T helper cell type 2 (Th2) effector apoptosis versus expansion. Th2- polarized effector cells were generated in vitro from naive CD4 T of T cell receptor transgenic mice, and then restimulated with or without peptide Ag plus Ag-presenting cells and cytokines. In the absence of added cytokines, effector cells cultured without Ag died of apoptosis after 4-7 d. Paradoxically, Ag both induced proliferation and high levels of cytokine synthesis and accelerated effector cell death. IL-2 directly induced proliferation of effectors, supported and prolonged Ag- induced proliferation, and partially blocked apoptosis. TGF-beta did not effect proliferation or influence cytokine secretion, but it also partially blocked apoptosis. Together, IL-2 and TGF-beta synergized to almost completely block apoptosis, resulting in prolonged effector expansion and leading to the accumulation of a large pool of specific effectors. When Ag and both cytokines were present, the effector population increased 10(4)-10(5) fold over 20 d of culture. The synergy of IL-2 and TGF-beta suggests that they interfere with programmed cell death by distinct mechanisms. Since Th2 effectors are specialized to help B cells develop into antibody-secreting plasma cells, these results suggest that the availability of Ag and of the cytokines IL-2 and TGF-beta is a key factor influencing the fate of Th2 effector cells and thus the size and duration of the primary antibody response.
Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Facebook Add to Reddit Reddit Add to Technorati Technorati Twitter What's this?

This article has been cited by other articles:

Filippi, C. M., Juedes, A. E., Oldham, J. E., Ling, E., Togher, L., Peng, Y., Flavell, R. A., von Herrath, M. G. (2008). Transforming Growth Factor-{beta} Suppresses the Activation of CD8+ T-Cells When Naive but Promotes Their Survival and Function Once Antigen Experienced: A Two-Faced Impact on Autoimmunity. Diabetes 57: 2684-2692 [Abstract] [Full Text]
Das, L., Levine, A. D. (2008). TGF-{beta} Inhibits IL-2 Production and Promotes Cell Cycle Arrest in TCR-Activated Effector/Memory T Cells in the Presence of Sustained TCR Signal Transduction. J. Immunol. 180: 1490-1498 [Abstract] [Full Text]
McKinstry, K. K., Golech, S., Lee, W.-H., Huston, G., Weng, N.-P., Swain, S. L. (2007). Rapid default transition of CD4 T cell effectors to functional memory cells. JEM 204: 2199-2211 [Abstract] [Full Text]
Zheng, S. G., Wang, J., Wang, P., Gray, J. D., Horwitz, D. A. (2007). IL-2 Is Essential for TGF-beta to Convert Naive CD4+CD25- Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells. J. Immunol. 178: 2018-2027 [Abstract] [Full Text]
Lee, C. G., Kang, H.-R., Homer, R. J., Chupp, G., Elias, J. A. (2006). Transgenic Modeling of Transforming Growth Factor-{beta}1: Role of Apoptosis in Fibrosis and Alveolar Remodeling.. Proc Am Thorac Soc 3: 418-423 [Abstract] [Full Text]
Ito, M., Minamiya, Y., Kawai, H., Saito, S., Saito, H., Nakagawa, T., Imai, K., Hirokawa, M., Ogawa, J.-i. (2006). Tumor-Derived TGFbeta-1 Induces Dendritic Cell Apoptosis in the Sentinel Lymph Node. J. Immunol. 176: 5637-5643 [Abstract] [Full Text]
Kalies, K., Blessenohl, M., Nietsch, J., Westermann, J. (2006). T Cell Zones of Lymphoid Organs Constitutively Express Th1 Cytokine mRNA: Specific Changes during the Early Phase of an Immune Response. J. Immunol. 176: 741-749 [Abstract] [Full Text]
Leveen, P., Carlsen, M., Makowska, A., Oddsson, S., Larsson, J., Goumans, M.-J., Cilio, C. M., Karlsson, S. (2005). TGF-{beta} type II receptor-deficient thymocytes develop normally but demonstrate increased CD8+ proliferation in vivo. Blood 106: 4234-4240 [Abstract] [Full Text]
Swain, S. L. (2005). Thanks for the Memory!. J. Immunol. 175: 4823-4826 [Full Text]
Kim, H.-P., Kim, B.-G., Letterio, J., Leonard, W. J. (2005). Smad-dependent Cooperative Regulation of Interleukin 2 Receptor {alpha} Chain Gene Expression by T Cell Receptor and Transforming Growth Factor-{beta}. J. Biol. Chem. 280: 34042-34047 [Abstract] [Full Text]
Zheng, S. G., Wang, J. H., Koss, M. N., Quismorio, F. Jr., Gray, J. D., Horwitz, D. A. (2004). CD4+ and CD8+ Regulatory T Cells Generated Ex Vivo with IL-2 and TGF-{beta} Suppress a Stimulatory Graft-versus-Host Disease with a Lupus-Like Syndrome. J. Immunol. 172: 1531-1539 [Abstract] [Full Text]
Li, J., Huston, G., Swain, S. L. (2003). IL-7 Promotes the Transition of CD4 Effectors to Persistent Memory Cells. JEM 198: 1807-1815 [Abstract] [Full Text]
Tiemessen, M. M., Kunzmann, S., Schmidt-Weber, C. B., Garssen, J., Bruijnzeel-Koomen, C. A. F. M., Knol, E. F., Van Hoffen, E. (2003). Transforming growth factor-{beta} inhibits human antigen-specific CD4+ T cell proliferation without modulating the cytokine response. Int Immunol 15: 1495-1504 [Abstract] [Full Text]
Nelson, B. H., Martyak, T. P., Thompson, L. J., Moon, J. J., Wang, T. (2003). Uncoupling of Promitogenic and Antiapoptotic Functions of IL-2 by Smad-Dependent TGF-{beta} Signaling. J. Immunol. 170: 5563-5570 [Abstract] [Full Text]
Zheng, S. G., Gray, J. D., Ohtsuka, K., Yamagiwa, S., Horwitz, D. A. (2002). Generation Ex Vivo of TGF-{beta}-Producing Regulatory T Cells from CD4+CD25- Precursors. J. Immunol. 169: 4183-4189 [Abstract] [Full Text]
Suresh, R., Vig, M., Bhatia, S., Goodspeed, E. P. B., John, B., Kandpal, U., Srivastava, S., George, A., Sen, R., Bal, V., Durdik, J. M., Rath, S. (2002). Pentoxifylline Functions As an Adjuvant In Vivo to Enhance T Cell Immune Responses by Inhibiting Activation-Induced Death. J. Immunol. 169: 4262-4272 [Abstract] [Full Text]
Ryon, J. J., Moss, W. J., Monze, M., Griffin, D. E. (2002). Functional and Phenotypic Changes in Circulating Lymphocytes from Hospitalized Zambian Children with Measles. CVI 9: 994-1003 [Abstract] [Full Text]
McKallip, R. J., Lombard, C., Martin, B. R., Nagarkatti, M., Nagarkatti, P. S. (2002). Delta 9-Tetrahydrocannabinol-Induced Apoptosis in the Thymus and Spleen as a Mechanism of Immunosuppression in Vitro and in Vivo. J. Pharmacol. Exp. Ther. 302: 451-465 [Abstract] [Full Text]
Leveen, P., Larsson, J., Ehinger, M., Cilio, C. M., Sundler, M., Sjostrand, L. J., Holmdahl, R., Karlsson, S. (2002). Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable. Blood 100: 560-568 [Abstract] [Full Text]
McKallip, R. J., Lombard, C., Fisher, M., Martin, B. R., Ryu, S., Grant, S., Nagarkatti, P. S., Nagarkatti, M. (2002). Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 100: 627-634 [Abstract] [Full Text]
Hussain, S. F., Anderson, C. F., Farber, D. L. (2002). Differential SLP-76 Expression and TCR-Mediated Signaling in Effector and Memory CD4 T Cells. J. Immunol. 168: 1557-1565 [Abstract] [Full Text]
Valladeau, J., Clair-Moninot, V., Dezutter-Dambuyant, C., Pin, J.-J., Kissenpfennig, A., Mattei, M.-G., Ait-Yahia, S., Bates, E. E. M., Malissen, B., Koch, F., Fossiez, F., Romani, N., Lebecque, S., Saeland, S. (2002). Identification of Mouse Langerin/CD207 in Langerhans Cells and Some Dendritic Cells of Lymphoid Tissues. J. Immunol. 168: 782-792 [Abstract] [Full Text]
Chen, W., Jin, W., Tian, H., Sicurello, P., Frank, M., Orenstein, J. M., Wahl, S. M. (2001). Requirement for Transforming Growth Factor {beta}1 in Controlling T Cell Apoptosis. JEM 194: 439-454 [Abstract] [Full Text]
Golstein, P., Wyllie, A. H. (2001). T Cell Death and Transforming Growth Factor {beta}1. JEM 194: f19-f22 [Full Text]
Cottrez, F., Groux, H. (2001). Regulation of TGF-{{beta}} Response During T Cell Activation Is Modulated by IL-10. J. Immunol. 167: 773-778 [Abstract] [Full Text]
Yamagiwa, S., Gray, J. D., Hashimoto, S., Horwitz, D. A. (2001). A Role for TGF-{{beta}} in the Generation and Expansion of CD4+CD25+ Regulatory T Cells from Human Peripheral Blood. J. Immunol. 166: 7282-7289 [Abstract] [Full Text]
Oliveira, J. G. G., Ramos, J. P., Xavier, P., Sampaio, S., Magalhaes, M. C., Mendes, A. A., Pestana, M. (2001). Microemulsion cyclosporin formulation, in contrast to the old formulation, widens the T lymphocyte subsets differences between stable and acute rejection of kidney transplants. Nephrol Dial Transplant 16: 1256-1261 [Abstract] [Full Text]
Sabzevari, H., Kantor, J., Jaigirdar, A., Tagaya, Y., Naramura, M., Hodge, J. W., Bernon, J., Schlom, J. (2001). Acquisition of CD80 (B7-1) by T Cells. J. Immunol. 166: 2505-2513 [Abstract] [Full Text]
Jelley-Gibbs, D. M., Lepak, N. M., Yen, M., Swain, S. L. (2000). Two Distinct Stages in the Transition from Naive CD4 T Cells to Effectors, Early Antigen-Dependent and Late Cytokine-Driven Expansion and Differentiation. J. Immunol. 165: 5017-5026 [Abstract] [Full Text]
Steigerwald-Mullen, P., Kurilla, M. G., Braciale, T. J. (2000). Type 2 Cytokines Predominate in the Human CD4+ T-Lymphocyte Response to Epstein-Barr Virus Nuclear Antigen 1. J. Virol. 74: 6748-6759 [Abstract] [Full Text]
Brunner, T., Kasibhatla, S., Pinkoski, M. J., Frutschi, C., Yoo, N. J., Echeverri, F., Mahboubi, A., Green, D. R. (2000). Expression of Fas Ligand in Activated T Cells Is Regulated by c-Myc. J. Biol. Chem. 275: 9767-9772 [Abstract] [Full Text]
Rogers, P. R., Dubey, C., Swain, S. L. (2000). Qualitative Changes Accompany Memory T Cell Generation: Faster, More Effective Responses at Lower Doses of Antigen. J. Immunol. 164: 2338-2346 [Abstract] [Full Text]
Haynes, L., Linton, P.-J., Eaton, S. M., Tonkonogy, S. L., Swain, S. L. (1999). Interleukin 2, but Not Other Common {gamma} Chain-Binding Cytokines, Can Reverse the Defect in Generation of Cd4 Effector T Cells from Naive T Cells of Aged Mice. JEM 190: 1013-1024 [Abstract] [Full Text]
Ahmadzadeh, M., Hussain, S. F., Farber, D. L. (1999). Effector CD4 T Cells Are Biochemically Distinct from the Memory Subset: Evidence for Long-Term Persistence of Effectors In Vivo. J. Immunol. 163: 3053-3063 [Abstract] [Full Text]
Rich, R. F., Green, W. R. (1999). Antiretroviral Cytolytic T-Lymphocyte Nonresponsiveness: FasL/Fas-Mediated Inhibition of CD4+ and CD8+ Antiviral T Cells by Viral Antigen-Positive Veto Cells. J. Virol. 73: 3826-3834 [Abstract] [Full Text]
Genestier, L., Kasibhatla, S., Brunner, T., Green, D. R. (1999). Transforming Growth Factor {beta}1 Inhibits Fas Ligand Expression and Subsequent Activation-induced Cell Death in T Cells via Downregulation of c-Myc. JEM 189: 231-239 [Abstract] [Full Text]
Rogers, P. R., Huston, G., Swain, S. L. (1998). High Antigen Density and IL-2 Are Required for Generation of CD4 Effectors Secreting Th1 Rather Than Th0 Cytokines. J. Immunol. 161: 3844-3852 [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]
Miner, K. T., Croft, M. (1998). Generation, Persistence, and Modulation of Th0 Effector Cells: Role of Autocrine IL-4 and IFN-{gamma}. J. Immunol. 160: 5280-5287 [Abstract] [Full Text]
Zuckerman, L. A., Pullen, L., Miller, J. (1998). Functional Consequences of Costimulation by ICAM-1 on IL-2 Gene Expression and T Cell Activation. J. Immunol. 160: 3259-3268 [Abstract] [Full Text]
Farber, D. L. (1998). Cutting Edge Commentary: Differential TCR Signaling and the Generation of Memory T Cells. J. Immunol. 160: 535-539 [Abstract] [Full Text]
Saeki, K., Yuo, A., Kato, M., Miyazono, K., Yazaki, Y., Takaku, F. (1997). Cell Density-dependent Apoptosis in HL-60 Cells, Which Is Mediated by an Unknown Soluble Factor, Is Inhibited By Transforming Growth Factor beta 1 and Overexpression of Bcl-2. J. Biol. Chem. 272: 20003-20010 [Abstract] [Full Text]
Zhang, X., Brunner, T., Carter, L., Dutton, R. W., Rogers, P., Bradley, L., Sato, T., Reed, J. C., Green, D., Swain, S. L. (1997). Unequal Death in T Helper Cell (Th)1 and Th2 Effectors: Th1, but not Th2, Effectors Undergo Rapid Fas/FasL-mediated Apoptosis. JEM 185: 1837-1849 [Abstract] [Full Text]