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Upon interaction with dendritic cells (DCs), naive CD4 T cells differentiate into distinct subsets and orchestrate the development of a physiological immune response. When uncontrolled by cellular and molecular mechanisms, CD4 T cells can also lead to immune mediated inflammatory diseases (IMIDs). Initially, these distinct CD4 T-cell subsets were defined according to the expression of a limited number of cytokines. Later it was revealed that CD4 T cells can acquire much more complex functional phenotypes than previously thought. Experimental data showed that the CD4 T-cell subset TH17 can secrete IFN-γ and IL-4, which are signature molecules of other T-cell subsets. Furthermore, some TH17 cells can also explore an anti-inflammatory fate and participate in the resolution of the immune response. A more flexible theory has therefore evolved with the scope to better represent the plastic biology of CD4 T cells. In this context, several aspects still remain unclear. The goal of this review is to discuss the role of extrinsic and intrinsic cellular and molecular mechanisms, which can drive the plasticity of TH17 cells. In particular, we will outline the role of DCs and the function of transcriptional factors in shaping the fate of TH17 cells towards either a pathogenic or a regulatory phenotype. Finally, we will discuss whether TH17 cell plasticity could be a target for new therapies for IMIDs. We indeed envision that when the cellular and molecular mechanisms controlling TH17 plasticity are known, new therapies, which aim to reset the immune system, will be developed. This will be achieved by either selectively depleting only the pathogenic TH17 cells or, if possible, re converting these cells from pathogenic to regulatory. This will overcome the challenge posed by the immune suppressive side effects caused by the current therapies, which impair the function of CD4 cells or delete all of them, to the detriment of the patient.

Upon interaction with dendritic cells (DCs), naïve CD4 T cells differentiate into distinct subsets and orchestrate the development of a physiological immune response. When uncontrolled by cellular and molecular mechanisms, CD4 T cells can also lead to immune mediated inflammatory diseases (IMIDs). Initially, these distinct CD4 T-cell subsets were defined according to the expression of a limited number of cytokines. Later it was revealed that CD4 T cells can acquire much more complex functional phenotypes than previously thought. Experimental data showed that the CD4 T-cell subset T