The immune system has evolved numerous mechanisms of peripheral T cell 
immunoregulation, including a network of regulatory T (Treg) cells, to modulate 
and down-regulate immune responses at various times and locations and in various 
inflammatory circumstances. Amongst these, naturally occurring CD4(+)CD25(+) 
Treg cells (nTreg) represent a major lymphocyte population engaged in the 
dominant control of self-reactive T responses and maintaining tolerance in 
several models of autoimmunity. CD4(+)CD25(+) Treg cells differentiate in the 
normal thymus as a functionally distinct subpopulation of T cells bearing a 
broad T cell receptor repertoire, endowing these cells with the capacity to 
recognize a wide range of self and nonself antigen specificities. The generation 
of CD4(+)CD25(+) Treg cells in the immune system is genetically controlled, 
influenced by antigen recognition, and various signals, in particular, cytokines 
such as interleukin-2 and transforming growth factor-beta1, control their 
activation, expansion, and suppressive effector activity. Functional abrogation 
of these cells in vivo or genetic defects that affect their development or 
function unequivocally promote the development of autoimmune and other 
inflammatory diseases in animals and humans. Recent progress has shed light on 
our understanding of the cellular and molecular basis of CD4(+)CD25(+) Treg 
cell-mediated immune regulation. This article discusses the relative 
contribution of CD4(+)CD25(+) nTreg cells in the induction of immunologic 
self-tolerance and provides a comprehensive overview of recent finding regarding 
the functional properties and effector mechanism of these cells, as revealed 
from various in vitro and in vivo models.