Foxp3+CD25+CD4+ natural regulatory T cells in dominant self‐tolerance and autoimmune disease

Summary: Naturally arising CD25 + CD4 + regulatory T (Treg) cells, most of which are produced by the normal thymus as a functionally mature T‐cell subpopulation, play key roles in the maintenance of immunologic self‐tolerance and negative control of a variety of physiological and pathological immune responses. Natural Tregs specifically express Foxp3, a transcription factor that plays a critical role in their development and function. Complete depletion of Foxp3‐expressing natural Tregs, whether they are CD25 + or CD25 – , activates even weak or rare self‐reactive T‐cell clones, inducing severe and widespread autoimmune/inflammatory diseases. Natural Tregs are highly dependent on exogenously provided interleukin (IL)‐2 for their survival in the periphery. In addition to Foxp3 and IL‐2/IL‐2 receptor, deficiency or functional alteration of other molecules, expressed by T cells or non‐T cells, may affect the development/function of Tregs or self‐reactive T cells, or both, and consequently tip the peripheral balance between the two populations toward autoimmunity. Elucidation of the molecular and cellular basis of this Treg‐mediated active maintenance of self‐tolerance will facilitate both our understanding of the pathogenetic mechanism of autoimmune disease and the development of novel methods of autoimmune disease prevention and treatment via enhancing and re‐establishing Treg‐mediated dominant control over self‐reactive T cells.