CD4⁺Foxp3⁺Regulatory T Cells in Immune Tolerance

Abstract

Peripheral regulatory T cell networks suppress immune responses in various inflammatory contexts and ultimately assure peripheral tolerance. Naturally-occurring CD4⁺ Treg cells (nTreg) represent a major lymphocyte population maintaining dominant self-tolerance and controlling a variety of pathological immune responses. These nTreg cells specifically express Foxp3, a transcription factor that plays a critical role in their development and function. Functional abrogation of Foxp3-expressing nTreg cells in vivo, or genetic defects that affect their development or function, unequivocally predisposes animals and humans to the onset of multi-organ autoimmune and inflammatory diseases. CD4⁺ nTreg cells differentiate in the thymus as a functionally distinct subset of T cells, although their post-thymic differentiation can occur from conventional T cells. These cells bear a broad T cell receptor repertoire endowing these cells with the capacity to recognize a wide spectrum of self and non-self Ag specificities. These nTreg cells are dependent on IL-2 for their fitness in the periphery. In addition, deficiency or functional alteration of other surface molecules expressed on immune cells, may affect the development/function of nTreg cells, and consequently favor the onset of autoimmunity. Recent studies have shed light in our understanding of the cellular and molecular basis of CD4⁺ nTreg cell–mediated active maintenance of self-tolerance immune regulation, and 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 autoreactive T cells. In this chapter, we discuss the contribution of CD4⁺ nTreg cells in the induction of immunologic self-tolerance in animal models and humans.