Regulatory T cells: key players in tolerance and autoimmunity

Abstract

CD4 + CD25 + regulatory T (TR) lymphocytes are essential to the maintenance of immunologic tolerance in the host. The discovery of Foxp3 as a transcription factor essential to the differentiation of TR ushered in detailed studies of the molecular mechanisms of TR cell development, peripheral homeostasis, and effector functions. In humans, loss of function mutations in genes that regulate T-cell development and function have been associated with TR cell deficiency or dysfunction and syndromes of autoimmunity and immune dysregulation. Augmentation of TR cells by immunotherapy and pharmacologic agents is a promising strategy for the treatment of allergic and autoimmune diseases.

Figure 1

Natural and induced T_R cell populations. Upper panel: natural (thymic) CD4⁺CD25⁺ T_R cells develop in the thymus, are exported to the periphery where they constitutively express Foxp3. Middle panel. CD4⁺CD25⁻Foxp3⁻ cells can be induced to differentiate into CD4⁺CD25⁺Foxp3⁺ induced T_R cells under special conditions including low antigen exposure, oral tolerance, and immunotherapy. Induction in vitro can be achieved by stimulation in the presence of TGF-beta. Lower panel. IL-10 secreting Tr1 and related T_R are Foxp3⁻ and are induced in vivo in a TGF-beta-dependent manner, usually in the context of high antigenic exposure such as exists in the gastrointestinal tract and in chronic infection.

Figure 2

Genetic lesions resulting in T_R cell deficiency/dysfunction and autoimmunity. A. Activation of effector T (T_eff) cells by antigen presenting cells (APC) triggers T_eff cell activation and IL-2 production. Signaling by the IL-2 /IL-2 receptor (IL-2R)/STAT5 pathway is essential for the competency of T_R cells and helps maintain high level expression of Foxp3. It enables the suppression by T_R cells of both APC and T_eff cell function. X denotes genetic defects associated with IPEX (Foxp3) and IPEX-like syndromes (IL-2Rα chain and STAT5b).