Further observations confirmed this and indicated that Th17 and Treg
responses arise in parallel, that a subset of FoxP3+ cells also express ROR-γt [139,140], and that ROR-γt and FoxP3 can interact directly [25,140,141] and indirectly  to suppress Th17 differentiation. It is now also apparent that IL-6 and IL-1β, acting via STAT3, promote a loss of FoxP3 expression and the induction of ROR-γt expression and IL-17 production in nTregs[25,143]. Whether iTregs are similarly prone to transdifferentiate into Th17-like cells is controversial [25,144]. The Selleck Pexidartinib intimate relationship described between murine Treg and Th17 cells is also present in humans, as FoxP3+ Tregs capable of IL-17 production have now been identified in humans [145,146]. Proinflammatory cytokines, in particular IL-1β, also promote IL-17 production by human Tregs[145–149]. It is currently unclear whether FoxP3+RORγt+ T cells retain their suppressive activity  or undergo a reversible loss of suppressive activity during the switch to IL-17 production . What is clear, however, is that Tregs display a higher than suspected degree of phenotypic-plasticity and may at times perform proinflammatory
effector functions. This is leading some authors to question their accepted status as a lineage of committed Tregs. It is notable that Th17 cells also display a degree of phenotypic instability and can convert to a Th1 phenotype in a STAT-4- and T-bet-dependent fashion [151–156]. selleck chemicals llc It is tempting to speculate upon the functional significance of this plasticity in relation
to the anti-inflammatory properties of Tregs. If the net effect of Th17/iTreg-inducing factors favours Th17 development during the initiation of a response, an initial wave of IL-17-producing cells generated during an acute response might be resistant to nTreg-mediated suppression. Indeed, via production of IL-6 and IL-21 they may subvert Treg-mediated suppression actively and facilitate expansion of Th1/Th2 polarized responses. However, CHIR-99021 if inflammation is not resolved, and the Th17 cells repeatedly re-encounter their antigen, their subsequent transition towards a Th1-like phenotype may increase their susceptibility to Treg-mediated suppression facilitating the resolution of inflammation. It seems almost incredible now that the Th1/Th2 paradigm sufficed to describe the majority of T cell responses for so long, and with the continuing discovery of new subsets [157,158] it appears that the mirage of the four-subset paradigm will be quick to pass. The high degree of plasticity inherent in certain phenotypes is becoming more apparent and the dynamic relationship between subsets more complex.