A negative role for phosphoinositide 3-kinase in T-cell antigen receptor function

Curr Biol. 1997 May 1;7(5):285-93. doi: 10.1016/s0960-9822(06)00151-5.


Background: A delicate balance between positive and negative regulatory mechanisms during T-cell activation determines the specificity and magnitude of an immune response. Phosphoinositide 3-kinase (PI 3-kinase) is activated by a diverse set of receptors that determine T-cell function, including the T-cell antigen receptor (TCR), the costimulatory receptor CD28, and negative regulators of T-cell activation such as CTLA-4. PI 3-kinase is also regulated by the haematopoietic cytokines that determine T-cell differentiation and lymphocyte proliferation. PI 3-kinase can thus dynamically influence the outcome of the immune reactions at various stages. In this study, we investigated the importance of PI 3-kinase in TCR-directed T-cell activation using activated or inhibitory versions of PI 3-kinase.

Results: Certain aspects of TCR responses such as the induction of transcriptional activity of AP1 and serum response factor were not affected by expression of the mutant forms of PI 3-kinase. We found, however, that PI 3-kinase profoundly influenced the transactivation capacity of 'nuclear factor of activated T cells' (NF-AT) elicited by the TCR: expression of an activated form of PI 3-kinase inhibited TCR-mediated NF-AT responses, whereas expression of a dominant negative mutant of PI 3-kinase potently enhanced TCR-controlled NF-AT induction. These effects of PI 3-kinase were not mediated by previously identified PI 3-kinase effectors, such as protein kinase B, a positive regulator of PI 3-kinase, or the GTPase Rac, and are therefore likely to involve a novel, as yet unknown, effector molecule.

Conclusions: Our results establish that PI 3-kinase can both positively and negatively regulate T-cell function, and uncover a previously unrecognized function for PI 3-kinase in T cells as a selective negative regulator of TCR-signalling events and therefore as a determinant of T-cell homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Antigens, CD
  • Antigens, Differentiation / metabolism
  • Apoptosis
  • CD28 Antigens / physiology
  • CTLA-4 Antigen
  • Chloramphenicol O-Acetyltransferase / biosynthesis
  • DNA-Binding Proteins / metabolism
  • GTP Phosphohydrolases / metabolism
  • GTP-Binding Proteins / metabolism
  • Humans
  • Immunoconjugates*
  • Jurkat Cells / physiology*
  • Lymphocyte Activation*
  • Models, Biological
  • Nuclear Proteins / metabolism
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptors, Antigen, T-Cell / physiology*
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / metabolism
  • Serum Response Factor
  • T-Lymphocytes / immunology
  • T-Lymphocytes / physiology*
  • Transcription Factor AP-1 / metabolism
  • Transcription, Genetic*
  • Transfection
  • rac GTP-Binding Proteins


  • Antigens, CD
  • Antigens, Differentiation
  • CD28 Antigens
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • DNA-Binding Proteins
  • Immunoconjugates
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Serum Response Factor
  • Transcription Factor AP-1
  • Abatacept
  • Chloramphenicol O-Acetyltransferase
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • GTP Phosphohydrolases
  • GTP-Binding Proteins
  • rac GTP-Binding Proteins