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

Nature Immunologyvolume 4pages182188 (2003) | Download Citation

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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.

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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).

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Affiliations

  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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https://doi.org/10.1038/ni884

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