CTLA-4 regulates the requirement for cytokine-induced signals in T(H)2 lineage commitment

Nat Immunol. 2003 Feb;4(2):182-8. doi: 10.1038/ni884. Epub 2003 Jan 13.


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 (T(H)2) cells. T(H)2 differentiation of cells deficient for both STAT6 and CTLA-4 is accompanied by induction of GATA-3 and the migration of T(H)2 cells to peripheral tissues. CTLA-4 deficiency also affects the balance of the nuclear factors NFATc1 and NFATc2, and enhances activation of NF-kappaB. These results suggest that CTLA-4 has a critical role in T cell differentiation and that STAT6-dependent T(H)2 lineage commitment and stabilization can be bypassed by increasing the strength of signaling through the T cell receptor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abatacept
  • Animals
  • Antigens, CD
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism*
  • CTLA-4 Antigen
  • Cell Differentiation
  • Cell Movement
  • Cytokines / metabolism*
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / metabolism
  • GATA3 Transcription Factor
  • Immunoconjugates*
  • Immunoglobulin Class Switching
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, Knockout
  • NF-kappa B / metabolism
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • STAT6 Transcription Factor
  • Signal Transduction
  • Th2 Cells / cytology
  • Th2 Cells / immunology*
  • Trans-Activators / biosynthesis
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / immunology
  • Transcription Factors / metabolism


  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Cytokines
  • DNA-Binding Proteins
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Immunoconjugates
  • NF-kappa B
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • Nfatc2 protein, mouse
  • Nuclear Proteins
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Abatacept