Natural and induced T CD4+CD25+FOXP3+ regulatory T cells.

Evidence has been accumulated to show that the forkhead/winged-helix transcription factor Foxp3 is a good marker for specialized CD4+ T cells that regulate immune responses to self as well as to a variety of foreign antigens including infectious or tumor antigens, alloantigens, allergens, and commensal antigens. It is now well established that CD4+CD25+Foxp3+ regulatory T cells encompass two categories of lymphocytes that are distinct in their origin, antigen specificity, as well as the stimuli driving their differentiation and homeostasis. Natural CD4+CD25+Foxp3+ regulatory T cells are an independent lineage generated in the thymus through major histocompatibility class II molecules-dependent MHC class high avidity interactions with their T cell receptor. They are specific for self-antigens. Adaptive or induced CD4+CD25+Foxp3+ regulatory T cells stem from mature CD4+CD25-Foxp3-precursors at the periphery following adequate stimulation. They have been shown to develop in vivo following suboptimal antigen stimulation, in situations characterized by chronic inflammation (autoimmunity, allergy, immune responses to tumors and transplants) and also as physiological actors of the mucosal immune system. Although major progress has been accomplished over the last years in our understanding of the central role of CD4+CD25+Foxp3+ regulatory T cells in the control of immune responses, major issues are still elusive. In particular, there are still no reliable phenotypic or functional markers that make it possible to distinguish between natural and induced CD25+Foxp3+ regulatory T cells.