As well as the maintenance of peripheral tolerance, IL-2 has also been WZ4002 side effects somewhat paradoxically described play an important role in driving the proliferative response of activated T cells and as a critical factor in the generation of an appropriate memory T cell response. IL-2 exerts these pleiotropic effects through interacting with the heterotrimeric IL-2 receptor complex comprised of a, b and common c chains expressed on the surface of activated T cells. The critical role for IL-2 in the maintenance of T cell tolerance is evident from studies on transgenic mice deficient for either the cytokine itself or its receptor. These mice develop profound autoimmunity characterized by an uncontrolled expansion of auto-reactive T cells. Further analysis has revealed the mechanistic basis for these observations, and uncovered the critical role of IL-2R signalling in maintaining the competitive fitness of peripheral regulatory T cells, and in the direct inhibition of Th17 cell responses. These observations are further underscored by the strong genetic linkage between mutations at both the IL-2 and IL2RA/ CD25 gene loci and several T cell mediated autoimmune diseases in humans. However, precisely how such polymorphisms confer susceptibility to autoimmunity remains incompletely understood. A number of specific CD25 alleles associated with autoimmune susceptibility occur in association with enhanced levels of the soluble form of the IL-2R alpha chain in the serum of patients. However, the functional consequences of these observations are unknown. Numerous examples of soluble cytokine receptors have been described to exert immunomodulatory effects in vivo. These range from antagonistic or agonistic effects on receptor signalling, to acting as ligand chaperones or carrier proteins. Although there have been several descriptions of sCD25 acting as an inhibitor of IL-2 induced T cell responses in vitro, whether it plays a similar role in vivo has not been determined. sCD25 is known to be generated as a result of proteolytic cleavage, largely from the surface of activated T cells and levels of CD25 ‘shedding’ are directly related to the rate of proliferation of activated T cells. The levels of systemic sCD25 in the steady state are known to be remarkably stable and as a consequence sCD25 has been used extensively as a biomarker reflecting inflammatory diseases and tumours characterized by T cell expansion. However, whether these increased levels of sCD25 play any direct role in modulating disease has not been fully investigated. In this study we demonstrate for the first time that sCD25 exacerbates experimental autoimmune encephalomyelitis. These effects are associated with the enhanced generation of Th17 type responses in the periphery and increased infiltration of both CD4+ Th1 and Th17 cell subsets into the central nervous system. Acts early during the Th17 developmental programme by inhibiting signalling downstream of the IL-2R through its ability to sequester local IL-2. These data identify a previously unappreciated role for sCD25 in the pathogenesis of autoimmune disease. Similar to other cytokine receptors expressed at the cell surface, the individual chains of the IL-2R are also known to exist in soluble form in serum. In particular, stable expression levels of soluble CD25 observed in healthy adults has underscored its clinical use as a biomarker for a variety of inflammatory conditions.