The BCL2A1 gene as a pre-T cell receptor-induced regulator of thymocyte survival

J Exp Med. 2005 Feb 21;201(4):603-14. doi: 10.1084/jem.20041924.

Abstract

The pre-T cell receptor (TCR) is expressed early during T cell development and imposes a tight selection for differentiating T cell progenitors. Pre-TCR-expressing cells are selected to survive and differentiate further, whereas pre-TCR(-) cells are "negatively" selected to die. The mechanisms of pre-TCR-mediated survival are poorly understood. Here, we describe the induction of the antiapoptotic gene BCL2A1 (A1) as a potential mechanism regulating inhibition of pre-T cell death. We characterize in detail the signaling pathway involved in A1 induction and show that A1 expression can induce pre-T cell survival by inhibiting activation of caspase-3. Moreover, we show that in vitro "knockdown" of A1 expression can compromise survival even in the presence of a functional pre-TCR. Finally, we suggest that pre-TCR-induced A1 overexpression can contribute to T cell leukemia in both mice and humans.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Caspase 3
  • Caspase Inhibitors
  • Cell Line
  • Cell Survival
  • Gene Expression Regulation
  • Genes, bcl-2 / physiology*
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell / etiology
  • Leukemia-Lymphoma, Adult T-Cell / metabolism
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Minor Histocompatibility Antigens
  • NF-kappa B / metabolism
  • Protein Kinase C / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, Antigen, T-Cell, alpha-beta
  • Signal Transduction
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / physiology*
  • Type C Phospholipases / metabolism

Substances

  • BCL2-related protein A1
  • Caspase Inhibitors
  • Membrane Glycoproteins
  • Minor Histocompatibility Antigens
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Antigen, T-Cell
  • Receptors, Antigen, T-Cell, alpha-beta
  • pre-T cell receptor alpha
  • Protein Kinase C
  • Type C Phospholipases
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3