Regulatory T cells in oral and self-tolerance

ABSTRACTSeveral mechanisms of immunologic tolerance have been proposed, including deletion, anergy and active suppression. Deletion and anergy have been reported based on data from both in vivo and in vitro experiments, but evidence to support the involvement of active suppression in tolerance has been elusive, principally because of the difficulty in defining regulatory T (Tr) cells with immunosuppressive activity. However, data characterizing the function of Tr cells has recently begun to emerge both from experiments in the field of oral tolerance and from others utilizing transgenic (Tg) mice. One such model which we described uses Tg mice expressing a foreign physiological soluble antigen, beef insulin (BI), while another uses T cell receptor (α/β) Tg mice, whose T cell receptors (TCR) are specific for ovalbumin (OVA). Using such models, adoptive transfer of the Tr clones specific for myelin basic protein (MBP) from orally tolerant mice into naive mice was shown to protect the animals from experimental autoimmune encephalomyelitis (EAE). Transforming growth factor-beta (TGF-β) has been shown to be responsible for the immuno-suppression. Tr clones functioning in self-tolerance have also been obtained from mice expressing TCR or BI transgenes. T cell cultures from OVA specific TCR expressing Tg mice were stimulated in the presence of interleukin-10 (IL-10) and OVA peptide to produce Tr clones. The Tr clones secreted IL-10 and TGF-β as immunosuppressive factors. Tr clones with a different characteristic have been obtained from BI Tg mice. Adoptive transfer of the Tr clones into normal mice suppressed the BI specific antibody response. These Tr clones have type II Th cytokine profile and produced TGF-β as an inhibitory cytokine. TGF-β production also led to functional bystander suppression in the BI Tg mice. These three different types of Tr clones show considerable heterogeneity in the cytokine profiles. Further investigation of Tr cells will be important for our understanding of autoimmunity and the development of tactics for the therapy of autoimmune disease