Diabetic Perspectives
| Rev Diabet Stud,
2006,
3(2):88-95 |
DOI 10.1900/RDS.2006.3.88 |
Death Pathways in T Cell Homeostasis and Their Role in Autoimmune Diabetes
Matthew A. Gronski1,  2
1Beirne Carter Center for Immunology Research, University of Virginia, Lane Road, Charlottesville, VA 22908, USA.
2SBDR, Gneisenaustr. 86, 47057 Duisburg, Germany.
Address correspondence to: Matthew Gronski, e-mail: gronski@virginia.edu
Keywords: type 1 diabetes, T cell, apoptosis, programmed cell death, mitochondria, death receptor, fas
Abstract
T cell apoptosis is a process necessary for central and peripheral tolerance. It ensures the proper removal of autoreactive T cells during thymic development as well as T cell homeostasis and the downregulation of immune responses against antigens in the periphery. Thus it is essential for the prevention of autoimmunity. Apoptotic pathways can be triggered by intrinsic (mitochondria-based) and extrinsic (receptor-based) stimuli. Both pathways involve a cascade of proteolytic enzymes called caspases whose activation commits the cell to death. In the periphery, autoreactive lymphocytes can be silenced by developmental arrest (anergy), or deleted by programmed cell death (apoptosis) through receptor-based activation-induced cell death (AICD). Central tolerance seems to rely more heavily on the mitochondria-based, T cell receptor (TCR)-stimulated apoptotic pathway, since thymocytes lacking the pro-apoptotic Bcl-2 family member Bim are resistant to TCR-induced apoptosis. Furthermore, defects in the intrinsic pathway of apoptosis may impair clonal deletion of autoreactive T cells. Several animal models exist in which impaired apoptosis results in autoimmunity. Here, we discuss data that suggest defects in T cell apoptosis in type 1 diabetes mellitus.
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