Nced levels observed in vivo are thought to be directly related to the magnitude T cell mediated inflammatory responses. However, recent analysis of specific autoimmune susceptibility alleles at the CD25 gene locus has uncovered a direct association between increased disease susceptibility, disease severity and increased levels of sCD25 [10,11]. These studies indicate that sCD25 may play an important mechanistic role in driving disease pathogenesis. As expression of all three chains of the IL-2R signalling 1676428 complex on the cell surface are known to be required for efficient IL-2 binding and the subsequent activation of downstream signalling events [25], whether sCD25 has any physiological relevance or is a mere by-product of T cell activation and expansion has remained controversial. Despite the lower affinity of CD25 for IL-2 when compared to the heterotrimeric IL-2R complex, sCD25 has been found to bind IL-2 efficiently and have immunomodulatory effects in vitro [10,26]. It is also possible that sCD25 may interact with an as yet unidentified accessory protein(s) in vivo to enhance its affinity for IL-2. Along those lines, it is noteworthy that soluble IL-1RII 
is known to have its affinity for IL-1a/b enhanced almost 100 fold through its interaction with soluble IL-1R Accessory protein [27]. Although monomeric sCD25 has a molecular weight in the region of 40 kDa, 25837696 it has previously been found to be present as part of a protein complex with a molecular weight in the region of 100 kDa in the synovial fluid of rheumatoid arthritis patients 
[28]. Although the accessory proteins involved in this complex were not identified, it was found to efficiently inhibit IL-2 mediated responses in vitro. Furthermore, sCD25 has been demonstrated to exist in get Fexinidazole homodimeric form, although whether this alters its relative affinity for IL-2 is unknown [29]. Studies are ongoing to determine whether sCD25 exerts its immunomodulatory effects in EAE through either oligomerization or binding accessory proteins in vivo. Numerous studies have previously investigated the role of sCD25 in modulating T cell responses in vitro. These reports have often led to conflicting results with sCD25 having been variously described to both inhibit and enhance T cell responses. To our knowledge, no previous studies have examined the role of increased sCD25 in the clinical severity of an auto-immune disease. As sCD25 has been previously examined with respect to multiple sclerosis in humans, we chose a murine model of this disease to examine in vivo effects of sCD25. While a number of groups have demonstrated the capacity of sCD25 to inhibit IL-2 mediated proliferation of CD8+ cytotoxic T cell lines [28,30], it is noteworthy that Maier et al. also demonstrated that sCD25 could inhibit IL-2 mediated STAT5 phosphorylation in primary CD4+ T cells while enhancing responses through the inhibition of activation induced cell death [10]. Our study further extends these in vitro findings and demonstrates that sCD25-mediated IQ 1 blockade of IL-2 signalling modulates T cell responses towards a Th17 phenotype.Given the established role of IL-2 in mediating Treg homeostasis in vivo [3], it is surprising that we did not observe any effects on Treg subsets in the presence of sCD25 in this study. Although we did not specifically examine whether sCD25 affected the suppressive function of Tregs, levels of Foxp3 expression both in vitro and in vivo clearly indicate that sCD25 did not impact Treg survival or pe.Nced levels observed in vivo are thought to be directly related to the magnitude T cell mediated inflammatory responses. However, recent analysis of specific autoimmune susceptibility alleles at the CD25 gene locus has uncovered a direct association between increased disease susceptibility, disease severity and increased levels of sCD25 [10,11]. These studies indicate that sCD25 may play an important mechanistic role in driving disease pathogenesis. As expression of all three chains of the IL-2R signalling 1676428 complex on the cell surface are known to be required for efficient IL-2 binding and the subsequent activation of downstream signalling events [25], whether sCD25 has any physiological relevance or is a mere by-product of T cell activation and expansion has remained controversial. Despite the lower affinity of CD25 for IL-2 when compared to the heterotrimeric IL-2R complex, sCD25 has been found to bind IL-2 efficiently and have immunomodulatory effects in vitro [10,26]. It is also possible that sCD25 may interact with an as yet unidentified accessory protein(s) in vivo to enhance its affinity for IL-2. Along those lines, it is noteworthy that soluble IL-1RII is known to have its affinity for IL-1a/b enhanced almost 100 fold through its interaction with soluble IL-1R Accessory protein [27]. Although monomeric sCD25 has a molecular weight in the region of 40 kDa, 25837696 it has previously been found to be present as part of a protein complex with a molecular weight in the region of 100 kDa in the synovial fluid of rheumatoid arthritis patients [28]. Although the accessory proteins involved in this complex were not identified, it was found to efficiently inhibit IL-2 mediated responses in vitro. Furthermore, sCD25 has been demonstrated to exist in homodimeric form, although whether this alters its relative affinity for IL-2 is unknown [29]. Studies are ongoing to determine whether sCD25 exerts its immunomodulatory effects in EAE through either oligomerization or binding accessory proteins in vivo. Numerous studies have previously investigated the role of sCD25 in modulating T cell responses in vitro. These reports have often led to conflicting results with sCD25 having been variously described to both inhibit and enhance T cell responses. To our knowledge, no previous studies have examined the role of increased sCD25 in the clinical severity of an auto-immune disease. As sCD25 has been previously examined with respect to multiple sclerosis in humans, we chose a murine model of this disease to examine in vivo effects of sCD25. While a number of groups have demonstrated the capacity of sCD25 to inhibit IL-2 mediated proliferation of CD8+ cytotoxic T cell lines [28,30], it is noteworthy that Maier et al. also demonstrated that sCD25 could inhibit IL-2 mediated STAT5 phosphorylation in primary CD4+ T cells while enhancing responses through the inhibition of activation induced cell death [10]. Our study further extends these in vitro findings and demonstrates that sCD25-mediated blockade of IL-2 signalling modulates T cell responses towards a Th17 phenotype.Given the established role of IL-2 in mediating Treg homeostasis in vivo [3], it is surprising that we did not observe any effects on Treg subsets in the presence of sCD25 in this study. Although we did not specifically examine whether sCD25 affected the suppressive function of Tregs, levels of Foxp3 expression both in vitro and in vivo clearly indicate that sCD25 did not impact Treg survival or pe.