Deltex1 is a target of the transcription factor NFAT that promotes T cell anergy

Immunity. 2009 Jul 17;31(1):72-83. doi: 10.1016/j.immuni.2009.04.017.

Abstract

The molecular process underlying T cell anergy is incompletely understood. Deltex1 (DTX1) is a Notch target with unknown physiological function. Here we show that Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1 therefore represents a component downstream of calcium-NFAT signaling that regulates T cell anergy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antigens, Differentiation / immunology
  • Antigens, Differentiation / metabolism
  • Autoimmunity / immunology
  • Clonal Anergy / genetics*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / immunology
  • Early Growth Response Protein 2 / immunology
  • Early Growth Response Protein 2 / metabolism
  • Immediate-Early Proteins / immunology
  • Immediate-Early Proteins / metabolism
  • Inflammation / immunology
  • Inflammation / metabolism
  • Liver / immunology
  • Liver / metabolism
  • Liver / pathology
  • Lung / immunology
  • Lung / metabolism
  • Lung / pathology
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • NFATC Transcription Factors / metabolism*
  • Proto-Oncogene Proteins c-cbl / immunology
  • Proto-Oncogene Proteins c-cbl / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Ubiquitin-Protein Ligases
  • Up-Regulation / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Cblb protein, mouse
  • DNA-Binding Proteins
  • Early Growth Response Protein 2
  • Egr2 protein, mouse
  • Gadd45b protein, mouse
  • Immediate-Early Proteins
  • Laptm5 protein, mouse
  • Membrane Proteins
  • NFATC Transcription Factors
  • Dtx1 protein, mouse
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases