Cell Death

Last February there was a series of three papers in Immunity on the contraction of the T cell response and the mechanisms of the two major cell death pathways. I have always found the process of cell death fascinating. Apoptosis: the programmed cell death brought about by signals that trigger the activation of a cascade of ‘suicide’ proteins in the cells destined to die. This was the first definition of cell death I learned, but as my education continued and as the scientific literature advanced the science of the cellular death pathway the definition has become more complex.

There are two known pathways of apoptosis; extrinsic and intrinsic. Extrinsic apoptosis: death ligands (FasL) bind to associative death receptors (Fas) on the cell surface triggering recruitment of varying molecules and eventual autocatalysis and subsequent cell degradation. Intrinsic apoptosis: Bcl-2 proteins, one of which is Bim, is an apoptosis pathway occurring near or within the mitochondria. Bim is a trigger of the mitochondrial pathway of apoptosis and plays a prominent role in cell death caused by cytokine deprivation of T cells. When these mechanisms of cell death do not operate properly autoimmune disease can result and have accelerated progression.

Hughes et. al. (2008) discovered overlapping roles for Fas and Bim in T cell death. Mice lacking both Fas and Bim mediated death had enhanced and accelerated fatal lymphadenopathy (disease or swelling of the lymph nodes) and autoimmunity relative to those lacking only one of the death proteins. Hutcheson et. al. (2008) focused on the progression of systemic lupus erythematosus (SLE) as it related to the balance of the two cell death pathways. Mice with defects in the two pathways developed severe SLE-like disease. Weant et. al. (2008) came to the similar conclusion that both death pathways concurrently prevent autoimmunity and regulate T cell response.

Green (2008) in his review of these three articles poses the question; there is a redundancy in the cell-death process, but who is backing up whom? He reviews literature that suggested the process of T cell clonal contraction during an immune response was due to limited growth and survival factors rather than active ligation of death receptors. These new studies highlight the essential combination of each pathway in the T cell clonal contraction process.