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CTLA-4 regulates the requirement for cytokine-induced signals in TH2 lineage commitment

Nature Immunologyvolume 4pages182188 (2003) | Download Citation



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.

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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


  1. UCSF Diabetes Center and Department of Medicine, University of California San Francisco, San Francisco, 94143, CA, USA

    • Hélène Bour-Jordan
    •  & Qizhi Tang
  2. Howard Hughes Medical Institute, University of California San Francisco, San Francisco, 94143, CA, USA

    • Jane L. Grogan
    •  & Richard M. Locksley
  3. Departments of Medicine and Microbiology-Immunology, University of California San Francisco, San Francisco, 94143, CA, USA

    • Jane L. Grogan
    •  & Richard M. Locksley
  4. The Committee on Immunology, University of Chicago, Chicago, 60637, IL, USA

    • Hélène Bour-Jordan
    • , Qizhi Tang
    •  & Jeffrey A. Bluestone
  5. Immunology Applications Core Facility, University of Chicago, Chicago, 60637, IL, USA

    • Julie A. Auger


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The authors declare no competing financial interests.

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Correspondence to Jeffrey A. Bluestone.

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