1. ¹Department of Microbiology and Immunology, Institute for Cellular Therapeutics, University of Louisville, Louisville, KY, USA
2. ²Frankel Laboratory for Experimental Bone Marrow Transplantation, Center for Stem Cell Research, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
3. ³Target-In Ltd, Petach Tikva, Israel

Correspondence: Dr Shai Yarkoni, Target-In Ltd, Shenkar Street 14, Petach Tikva, Israel. E-mail: yarkoni@target-in.com

Received 28 April 2008; Revised 25 July 2008; Accepted 28 July 2008; Published online 16 September 2008.

Abstract

Activation-induced cell death is a general mechanism of immune homeostasis through negative regulation of clonal expansion of activated immune cells. This mechanism is involved in the maintenance of self- and transplant tolerance through polarization of the immune responses. The Fas/Fas-ligand interaction is a major common executioner of apoptosis in lymphocytes, with a dual role in regulatory T cell (Treg) function: Treg cell homeostasis and Treg cell-mediated suppression. Sensitivity to apoptosis and the patterns of Treg-cell death are of outmost importance in immune homeostasis that affects the equilibrium between cytolytic and suppressor forces in activation and termination of immune activity. Naive innate (naturally occurring) Treg cells present variable sensitivities to apoptosis, related to their turnover rates in tissue under steady state conditions. Following activation, Treg cells are less sensitive to apoptosis than cytotoxic effector subsets. Their susceptibility to apoptosis is influenced by cytokines within the inflammatory environment (primarily interleukin-2), the mode of antigenic stimulation and the proliferation rates. Here, we attempt to resolve some controversies surrounding the sensitivity of Treg cells to apoptosis under various experimental conditions, to delineate the function of cell death in regulation of immunity.