Molecular mechanisms that dictate the differentiation of Th17 cells in autoimmunity
Final Report Abstract
We characterized a population of CD4+ T helper cells that concomitantly expresses IL-17 and IFN-y. Those cells arise specifically in the presence of IL-23 and IL-23R signaling is crucial for the development of those cells. Using triple reporter mice, we established that IL-17+ IFN-y+ T cells are highly pathogenic - they express high levels of GM-CSF, a cytokine recognized to be pathogenic and inflammatory, and also contain the highest number of MOG-peptide-specific T cells in the CNS of mice with EAE. This demonstrates that double-producing cells, present in the inflammatory lesions in autoimmune diseases are responsible for the antigen-specific reactivation and consequently tissue destruction. We demonstrate that although these cells express IFN-y and T-bet, their pathogenicity is independent of T-bet (as well as other Th-1 associated transcription factors), which suggests that albeit modulation of T-bet might be important for Th1-mediated autoimmunity, it might be less effective in the control of Th17-mediated symptoms. Th17 cells are plastic and can acquire a Th1 phenotype (ex-Th17 cells). Furthermore, the cells can revert under the influence of IL-23 to regain their initial cytokine expression. Although Th1 and ex-Th17 cells might be functionally similar, they differ in the expression of cytokine receptors and transcription factors. Thus they will switch to a different state when exposed to different microenvironments. We were surprised about the results with the AhRKO animals, which can be explained by an effect of our animal facility. It is know that the gut microbiota plays a major role in harnessing the immune system and differences in the environment can have a big impact on disease susceptibility and cytokine expression. This demonstrated again the difficulty to reproduce some published data and the major influence of the environment on the immune system. It is indispensable to not only consider “statistical significance” (which can be reached by increasing the number of animals in an experiment or the number of repeats) but also “biological relevance” - which is more meaningful, more reliable and perhaps easier to compare between different research institutions.
Publications
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Cutting edge: the pathogenicity of IFN-g-producing Th17 cells is independent of T-bet. J Immunol, 2013. 190(9): p. 4478-82
Duhen R, Glatigny S, Arbelaez CA, Blair TC, Oukka M, Bettelli E
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Integrin alpha L controls the homing of regulatory T cells during CNS autoimmunity in the absence of integrin alpha 4. Scientific reports, 2015. 5: p. 7834
Glatigny S, Duhen R, Arbelaez CA, Kumari S, Bettelli E
