Lee, Y. et al. Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 13, 991-999

1] Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2].
Nature Immunology (Impact Factor: 20). 09/2012; 13(10):991-9. DOI: 10.1038/ni.2416
Source: PubMed


Interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) are often present at the sites of tissue inflammation in autoimmune diseases, which has led to the conclusion that T(H)17 cells are main drivers of autoimmune tissue injury. However, not all T(H)17 cells are pathogenic; in fact, T(H)17 cells generated with transforming growth factor-β1 (TGF-β1) and IL-6 produce IL-17 but do not readily induce autoimmune disease without further exposure to IL-23. Here we found that the production of TGF-β3 by developing T(H)17 cells was dependent on IL-23, which together with IL-6 induced very pathogenic T(H)17 cells. Moreover, TGF-β3-induced T(H)17 cells were functionally and molecularly distinct from TGF-β1-induced T(H)17 cells and had a molecular signature that defined pathogenic effector T(H)17 cells in autoimmune disease.

Download full-text


Available from: David A Hafler,
  • Source
    • "To confirm that Th17 plasticity contributed to the pathogenic profile of T cells primed with DC-Il2 À/À cells, we investigated whether Th17 cells differentiated under conditions of IL-2 deficiency exhibited the pathogenic signature that has been associated with immune pathology across several settings (Lee et al., 2012). Within these settings, IL-23 contributes to the emergence of pathogenic Th17 effector cells (Wu et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Th17 cells express diverse functional programs while retaining their Th17 identity, in some cases exhibiting a stem-cell-like phenotype. Whereas the importance of Th17 cell regulation in autoimmune and infectious diseases is firmly established, the signaling pathways controlling their plasticity are undefined. Using a mouse model of invasive pulmonary aspergillosis, we found that lung CD103(+) dendritic cells (DCs) would produce IL-2, dependent on NFAT signaling, leading to an optimally protective Th17 response. The absence of IL-2 in DCs caused unrestrained production of IL-23 and fatal hyperinflammation, which was characterized by strong Th17 polarization and the emergence of a Th17 stem-cell-like population. Although several cell types may be affected by deficient IL-2 production in DCs, our findings identify the balance between IL-2 and IL-23 productions by lung DCs as an important regulator of the local inflammatory response to infection.
    Cell Reports 09/2015; 12(11). DOI:10.1016/j.celrep.2015.08.030 · 8.36 Impact Factor
  • Source
    • "Melatonin also increased the expression of IL-10, associated to non-pathogenic Th17 cells (Lee et al., 2012; McGeachy et al., 2007) (Figures 4A and 4B). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Seasonal changes in disease activity have been observed in multiple sclerosis, an autoimmune disorder that affects the CNS. These epidemiological observations suggest that environmental factors influence the disease course. Here, we report that melatonin levels, whose production is modulated by seasonal variations in night length, negatively correlate with multiple sclerosis activity in humans. Treatment with melatonin ameliorates disease in an experimental model of multiple sclerosis and directly interferes with the differentiation of human and mouse T cells. Melatonin induces the expression of the repressor transcription factor Nfil3, blocking the differentiation of pathogenic Th17 cells and boosts the generation of protective Tr1 cells via Erk1/2 and the transactivation of the IL-10 promoter by ROR-α. These results suggest that melatonin is another example of how environmental-driven cues can impact T cell differentiation and have implications for autoimmune disorders such as multiple sclerosis.
    Cell 09/2015; 162(6):1338-1352. DOI:10.1016/j.cell.2015.08.025 · 32.24 Impact Factor
    • "Melatonin also increased the expression of IL-10, associated to non-pathogenic Th17 cells (Lee et al., 2012; McGeachy et al., 2007) (Figures 4A and 4B). "

    Seminars in Immunopathology 08/2015; DOI:10.1007/s00281-015-0521-5 · 7.75 Impact Factor
Show more