Depletion of Tregs facilitated the emergence of an IL-17 response [102], proving that IL-6 is critical in determining the outcome of immunization. Generation of a Th17 response in IL-6 knock-out mice also established the existence of an IL-6-independent route to Th17 priming which is dependent upon the autocrine production of IL-21 by T cells [102,103]. The role of TLR-stimuli in inducing selleckchem the IL-6

production that determines whether Treg or Th17 responses develop was illustrated further by the fact that immunization with MOG in incomplete Freund’s adjuvant (IFA) leads to a MOG-reactive Treg response, while immunization with MOG in complete Freund’s adjuvant (CFA) (in which heat-killed Mycobaterium tuberculosis is the source of the TLR ligands) results in Th17 polarization [104]. However, TLR-stimulation may not be required to promote IL-6 production once Th17 effector cells have been generated; therefore, effector cytokine production in the absence of infection may exacerbate Crenolanib manufacturer inflammation, both directly and by retarding Treg function. In this respect, production of IL-6 has been implicated in preventing efficient regulation

of effector responses in the CNS during EAE [69]. Other proinflammatory cytokines that have been shown to overcome Treg-mediated suppression are TNF-α, IL-7 and IL-15 [69,105–108], all of which have also been suggested to promote Th17 responses [6,109,110], emphasizing further the tight regulation between Tregs and Th17 cells. Changes in the balance of effector versus regulatory T cells on a local basis precede the development of diabetes in non-obese diabetic (NOD) mice. Onset of disease correlates with a progressive decrease in the Treg : T effector cell ratio in the inflamed islets which is not reflected in old the draining pancreatic lymph node [111]. Whether this change resulted from the selective death of Tregs[111], ineffective

regulatory function or resistance to regulation within the effector population was unclear. It has since been reported that the poor efficiency of Treg-mediated suppression in NOD mice or patients with type 1 diabetes is not due to intrinsic Treg defects, but rather to effector T cells becoming resistant to regulation [112–114]. This resistance was associated with IL-21 production by effector T cells, which could block Treg function both in vivo and in vitro[115]. IL-21 has also been shown to prevent the TGF-β-induced expression of FoxP3 in naive T cells and favour Th17 development [116]. It seems pertinent that cytokines produced by and promoting the development of Th17 cells – IL-6 and IL-21 [117]– inhibit Treg function. Distinct degrees of susceptibility to a particular means of suppression may also provide the basis of differential responsiveness among effector subsets.