CAML regulates Bim-dependent thymocyte death

• Published in: Cell death and differentiation Vol. 17; no. 10; pp. 1566 - 1576
• Main Authors: Edgar, C E, Lindquist, L D, McKean, D L, Strasser, A, Bram, R J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2010; Nature Publishing Group
• Subjects: 631/80/82; 692/698/1543/1565/1597/554; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antigens; Apoptosis; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell death; Cytokines; Endoplasmic reticulum; Etoposide - pharmacology; fas Receptor - metabolism; Life Sciences; Ligands; Lymphocytes; Medicine; Membrane Proteins - metabolism; Mice; original-paper; Pediatrics; Peptides; Proteins; Proto-Oncogene Proteins - metabolism; Reactive Oxygen Species - metabolism; Stem Cells; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Tumor Suppressor Protein p53 - metabolism; United States > US; CAML; T-cell development; ROS; Bim
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2010.30

Appropriate control of apoptosis during T lymphocyte differentiation is critical for destruction of T cells bearing potentially autoreactive or useless immuno-receptors and for survival of those T cells bearing antigen receptors that may recognize foreign proteins. Despite the well-established importance of thymocyte survival, the exact signals regulating thymocyte apoptosis have not been fully elucidated. Here, we show that thymocytes lacking the endoplasmic reticulum protein calcium-modulating cyclophilin ligand (CAML) failed to undergo normal T-cell development and exhibited dramatically increased rates of apoptosis.
In vitro
, CAML-deficient thymocytes accumulated high levels of reactive oxygen species (ROS) and underwent abnormally accelerated death in response to several cytotoxic stimuli, including treatment with etoposide, cytokine deprivation, or Fas ligation. Although neither p53 deletion nor loss of Fas rescued the survival and continued development of CAML-deficient thymocytes, removal of the pro-apoptotic BH3-only Bcl-2 family member Bim significantly restored their survival. This work reveals CAML to be a critically important regulator of ROS- and Bim-dependent thymocyte death.