FADD/MORT1 regulates the pre-TCR checkpoint and can function as a tumour suppressor

EMBO J. 2000 Mar 1;19(5):931-41. doi: 10.1093/emboj/19.5.931.

Abstract

Productive rearrangement of the T-cell receptor (TCR) beta gene and signalling through the pre-TCR-CD3 complex are required for survival, proliferation and differentiation of T-cell progenitors (pro-T cells). Here we identify a role for death receptor signalling in early T-cell development using a dominant-negative mutant of the death receptor signal transducer FADD/MORT1 (FADD-DN). In rag-1(-/-) thymocytes, which are defective in antigen receptor gene rearrangement, FADD-DN bypassed the requirement for pre-TCR signalling, promoting pro-T-cell survival and differentiation to the more mature pre-T stage. Surprisingly, differentiation was not accompanied by the proliferation that occurs normally during transition to the pre-T stage. Consistent with a role for FADD/MORT1 in this cell division, FADD-DN rag-1(-/-) pro-T cells failed to proliferate in response to CD3epsilon ligation. Concomitant signalling through the pre-TCR and death receptors appears to trigger pro-T cell survival, proliferation and differentiation, whereas death receptor signalling in thymocytes that lack a pre-TCR induces apoptosis. Later in life all FADD-DN rag-1(-/-) mice developed thymic lymphoma, indicating that FADD/MORT1 can act as a tumour suppressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology
  • Carrier Proteins / genetics*
  • Carrier Proteins / immunology
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Division / genetics
  • Cell Division / immunology
  • Fas-Associated Death Domain Protein
  • Gene Expression Regulation
  • Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
  • Genes, Tumor Suppressor
  • Mice
  • Receptors, Antigen, T-Cell, alpha-beta / genetics*
  • Receptors, Antigen, T-Cell, alpha-beta / immunology*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • Receptors, Antigen, T-Cell, alpha-beta