Immune Homeostasis Maintained by Tregs, pp. 201-223
Authors: (Myoung-Ho Jang, Yun-Jae Jung, Hyung-Ran Kim, Byung-In Moon, Ju-Young Seoh, Laboratory of Gastrointestinal Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan, and others)
Abstract: Regulatory T cells (Tregs) play a key role in the maintenance of immune homeostasis in vivo. The unique characteristics of Tregs endowed by foxp3, inability to produce IL-2 while constitutively expressing IL-2Rα (CD25), make themselves absolutely dependent on the responding cells for IL-2. When IL-2 is produced and secreted by the responder cells, it would bind preferentially to IL-2Rs on nearby Tregs, as the density of IL-2R on Tregs is higher than that on the responding cells. Therefore, Tregs start to proliferate earlier than the responding cells, and suppress the latter, resulting in an elegant loop of negative feedback. Furthermore, Tregs suppress the responder cells by lowering the production of IL-2 as well as by inducing earlier shedding of IL-2Rα from the responding cells. Meanwhile, the fate of secreted IL-2 and the mode of suppression are different according to the concentration of IL-2; if the stimulating signal is weak, a small amount of IL-2 is secreted from the responder cells and will bind preferentially to the IL-2Rs on Tregs. Therefore, Tregs will proliferate earlier and suppress the responder cells. If the stimulating signal is strong and the initially secreted IL-2 is enough, it would also bind to the IL-2Rs on the responder cells. In this case, the responder cells proliferate initially, but their late expansion is suppressed by Tregs. Either way, in the steady state, Tregs always win the responder cells in the competition for IL-2, hence the state of tolerance. However, in infection or inflammatory state, the suppressive activities of Tregs are suppressed (contra-suppression) by certain molecules secreted from the innate immune cells (i.e., dendritic cells), such as IL-6 or IL-21, resulting in the proliferation of the responder cells, hence immune response is elicited. In conclusion, regulation of IL-2 and IL-2Rα is an important mechanism of immune homeostasis maintained by Tregs.
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