Abstract
The relative importance of the cytokine milieu versus cytolytic T lymphocyte-associated antigen 4 (CTLA-4) and T cell receptor signal strength on T cell differentiation remains unclear. Here we have generated mice deficient for signal transducer and activator of transcription 6 (STAT6) and CTLA-4 to determine the role of CTLA-4 in cytokine-driven T cell differentiation. CTLA-4–deficient T cells bypass the need for STAT6 in the differentiation of T helper type 2 (TH2) cells. TH2 differentiation of cells deficient for both STAT6 and CTLA-4 is accompanied by induction of GATA-3 and the migration of TH2 cells to peripheral tissues. CTLA-4 deficiency also affects the balance of the nuclear factors NFATc1 and NFATc2, and enhances activation of NF-κB. These results suggest that CTLA-4 has a critical role in T cell differentiation and that STAT6-dependent TH2 lineage commitment and stabilization can be bypassed by increasing the strength of signaling through the T cell receptor.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hou, J. et al. An interleukin-4-induced transcription factor: IL-4 Stat. Science 265, 1701–1706 (1994).
Quelle, F.W. et al. Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis. Mol. Cell. Biol. 15, 3336–3343 (1995).
Zheng, W. & Flavell, R.A. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997).
Zhang, D.H., Cohn, L., Ray, P., Bottomly, K. & Ray, A. Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J. Biol. Chem. 272, 21597–21603 (1997).
Shimoda, K. et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380, 630–633 (1996).
Takeda, K. et al. Essential role of Stat6 in IL-4 signalling. Nature 380, 627–630 (1996).
Hosken, N.A., Shibuya, K., Heath, A.W., Murphy, K.M. & O'Garra, A. The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-αβ-transgenic model. J. Exp. Med. 182, 1579–1584 (1995).
Lenschow, D.J. et al. CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes. Immunity 5, 285–293 (1996).
Rulifson, I.C., Sperling, A.I., Fields, P.E., Fitch, F.W. & Bluestone, J.A. CD28 costimulation promotes the production of Th2 cytokines. J. Immunol. 158, 658–665 (1997).
Kato, T. & Nariuchi, H. Polarization of naive CD4+ T cells toward the Th1 subset by CTLA-4 costimulation. J. Immunol. 164, 3554–3562 (2000).
Khattri, R., Auger, J.A., Griffin, M.D., Sharpe, A.H. & Bluestone, J.A. Lymphoproliferative disorder in CTLA-4 knockout mice is characterized by CD28-regulated activation of Th2 responses. J. Immunol. 162, 5784–5791 (1999).
Oosterwegel, M.A. et al. The role of CTLA-4 in regulating Th2 differentiation. J. Immunol. 163, 2634–2639 (1999).
Tivol, E.A. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541–547 (1995).
Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 270, 985–988 (1995).
Croft, M., Bradley, L.M. & Swain, S.L. Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. J. Immunol. 152, 2675–2685 (1994).
London, C.A., Lodge, M.P. & Abbas, A.K. Functional responses and costimulator dependence of memory CD4+ T cells. J. Immunol. 164, 265–272 (2000).
Chambers, C.A., Sullivan, T.J. & Allison, J.P. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 7, 885–895 (1997).
Kim, J.I., Ho, I.C., Grusby, M.J. & Glimcher, L.H. The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. Immunity 10, 745–751 (1999).
Grogan, J.L. et al. Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity 14, 205–215 (2001).
Mohrs, M., Shinkai, K., Mohrs, K. & Locksley, R.M. Analysis of type 2 immunity in vivo with a bicistronic IL-4 reporter. Immunity 15, 303–311 (2001).
Ranger, A.M. et al. Delayed lymphoid repopulation with defects in IL-4-driven responses produced by inactivation of NF-ATc. Immunity 8, 125–134 (1998).
Yoshida, H. et al. The transcription factor NF-ATc1 regulates lymphocyte proliferation and Th2 cytokine production. Immunity 8, 115–124 (1998).
Ranger, A.M., Oukka, M., Rengarajan, J. & Glimcher, L.H. Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development. Immunity 9, 627–635 (1998).
Rengarajan, J., Tang, B. & Glimcher, L.H. NFATc2 and NFATc3 regulate TH2 differentiation and modulate TCR-responsiveness of naive TH cells. Nature Immunol. 3, 48–54 (2002).
Das, J. et al. A critical role for NF-κB in Gata3 expression and Th2 differentiation in allergic airway inflammation. Nature Immunol. 2, 45–50 (2001).
Fraser, J.H., Rincon, M., McCoy, K.D. & Le Gros, G. CTLA4 ligation attenuates AP-1, NFAT and NF-κB activity in activated T cells. Eur. J. Immunol. 29, 838–844 (1999).
Olsson, C., Riesbeck, K., Dohlsten, M., Michaelsson, E. & Riebeck, K. CTLA-4 ligation suppresses CD28-induced NF-κB and AP-1 activity in mouse T cell blasts. J. Biol. Chem. 274, 14400–14405 (1999).
Wang, L.M. et al. IRS-1: essential for insulin- and IL-4-stimulated mitogenesis in hematopoietic cells. Science 261, 1591–1594 (1993).
Sun, X.J. et al. Role of IRS-2 in insulin and cytokine signalling. Nature 377, 173–177 (1995).
Jeppson, J.D. et al. Requirement for dual signals by anti-CD40 and IL-4 for the induction of NF-κB, IL-6, and IgE in human B lymphocytes. J. Immunol. 161, 1738–1747 (1998).
Tinnell, S.B., Jacobs-Helber, S.M., Sterneck, E., Sawyer, S.T. & Conrad, D.H. STAT6, NF-κB and C/EBP in CD23 expression and IgE production. Int. Immunol. 10, 1529–1538 (1998).
Pioli, C., Gatta, L., Ubaldi, V. & Doria, G. Inhibition of IgG1 and IgE production by stimulation of the B cell CTLA-4 receptor. J. Immunol. 165, 5530–5536 (2000).
Kaplan, M.H., Schindler, U., Smiley, S.T. & Grusby, M.J. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4, 313–319 (1996).
Dent, A.L., Hu-Li, J., Paul, W.E. & Staudt, L.M. T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6. Proc. Natl. Acad. Sci. USA 95, 13823–13828 (1998).
Dent, A.L., Doherty, T.M., Paul, W.E., Sher, A. & Staudt, L.M. BCL-6-deficient mice reveal an IL-4-independent, STAT6-dependent pathway that controls susceptibility to infection by Leishmania major. J. Immunol. 163, 2098–2103 (1999).
Ouyang, W. et al. Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity 12, 27–37 (2000).
Finkelman, F.D. et al. Stat6 regulation of in vivo IL-4 responses. J. Immunol. 164, 2303–2310 (2000).
Jankovic, D. et al. Single cell analysis reveals that IL-4 receptor/Stat6 signaling is not required for the in vivo or in vitro development of CD4+ lymphocytes with a Th2 cytokine profile. J. Immunol. 164, 3047–3055 (2000).
Marengere, L.E. et al. Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. Science 272, 1170–1173 (1996).
Lee, K.M. et al. Molecular basis of T cell inactivation by CTLA-4. Science 282, 2263–2266 (1998).
Rodriguez-Palmero, M., Hara, T., Thumbs, A. & Hunig, T. Triggering of T cell proliferation through CD28 induces GATA-3 and promotes T helper type 2 differentiation in vitro and in vivo. Eur. J. Immunol. 29, 3914–3924 (1999).
Harlin, H. et al. CTLA-4 engagement regulates NF-κB activation in vivo. Eur. J. Immunol. 32, 2095–2104 (2002).
Shen, C.H. & Stavnezer, J. Interaction of stat6 and NF-κB: direct association and synergistic activation of interleukin-4-induced transcription. Mol. Cell. Biol. 18, 3395–3404 (1998).
Brogdon, J.L., Leitenberg, D. & Bottomly, K. The potency of TCR signaling differentially regulates NFATc/p activity and early IL-4 transcription in naive CD4+ T cells. J. Immunol. 168, 3825–3832 (2002).
Smith, J.A., Tang, Q. & Bluestone, J.A. Partial TCR signals delivered by FcR-nonbinding anti-CD3 monoclonal antibodies differentially regulate individual Th subsets. J. Immunol. 160, 4841–4849 (1998).
Tang, Q. et al. The Src family kinase Fyn mediates signals induced by TCR antagonists. J. Immunol. 168, 4480–4487 (2002).
Salomon, B. et al. Development of spontaneous autoimmune peripheral polyneuropathy in b7-2-deficient nod mice. J. Exp. Med. 194, 677–684 (2001).
Acknowledgements
We thank J. Arcella and P. Weghfart for animal care; M. Grusby for providing the STAT6−/− mice; A. Rosenberg, H. Thompson and T.S. Li for technical support; K. Shinkai and S. Chikuma for discussions; and members of the Bluestone laboratory for reading the manuscript. Supported by grants from the National Institutes of Health (Q.T) and the Juvenile Diabetes Research Foundation (H.B.J).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Bour-Jordan, H., Grogan, J., Tang, Q. et al. CTLA-4 regulates the requirement for cytokine-induced signals in TH2 lineage commitment. Nat Immunol 4, 182–188 (2003). https://doi.org/10.1038/ni884
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni884
This article is cited by
-
Association of CTLA-4 gene promoter polymorphisms with systemic sclerosis in Iranian population
Genes & Immunity (2006)
-
CD28-mediated co-stimulation: a quantitative support for TCR signalling
Nature Reviews Immunology (2003)
-
SOCS-3 regulates onset and maintenance of TH2-mediated allergic responses
Nature Medicine (2003)