The Transcription Factors T-bet and Runx Are Required for the Ontogeny of Pathogenic Interferon-γ-Producing T Helper 17 Cells

Abstract

SUMMARY T helper 17 (Th17) cells can give rise to interleukin-17A (IL-17A) and interferon (IFN)-γ-double producing cells that are implicated in development of autoimmune diseases. However, the molecular mechanisms that govern generation of IFN-γ-producing Th17 cells are unclear. We found that co-expression of the Th1- and Th17-cell master transcription factors, T-bet and retinoid-related orphan receptor gamma-t (RORγt), respectively, did not generate Th cells with robust IL-17 and IFN-γ expression. Instead, development of IFN-γ-producing Th17 cells required T-bet and Runx1 or Runx3. IL-12-stimulated Th17 cells upregulated Runx1, which bound to the Ifng locus in a T-bet dependent manner. Reciprocally, T-bet or Runx1 deficiency, or inhibition of Runx transcriptional activity, impaired the development of IFN-γ-producing Th17 cells, during experimental autoimmune encephalomyelitis, which correlated with substantially ameliorated disease course. Thus, our studies identify a critical role for T-bet and Runx transcription factors in the generation of pathogenic IFN-γ-producing Th17 cells.

Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis

“…Our finding that T-bet expression by Th17 cells is required for their transition to Th1-like cells and colitis pathogenesis is concordant with a recent study that identified a similar requirement for T-bet, as well as Runx factors, in experimental autoimmune encephalomyelitis (EAE) mediated by Th17 cells transfers (16). Interestingly, other studies suggest that T-bet expression by T cells is not absolutely required for EAE pathogenesis, although disease was blunted in its absence (31,32).…”

“…However, a role for IL-23-dependent IFN-γ production in the inflamed CNS was reported (27), suggesting the emergence of Th1-like cells from Th17 precursors may be a common feature of these two diseases. Nevertheless, a uniform deficit of single IFN-γ + cells in the absence of T-bet supports a central role for T-bet in the generation of this population, indicating that T-bet is required to fully inhibit Rorc and the Il17a/Il17f gene locus and completion of the transition to Th1-like cells (15,16). The mechanism by which dual IL-17A + IFN-γ + cells arise in the absence of T-bet and what role they play in colitis is a subject for future studies, especially in view of their possible association with disease in T-bet sufficient mice (9).…”

“…Specifically, developing Th17 cells can diverge to acquire Th1-like features contingent on IL-12 or IL-23 signaling, both of which activate Stat4 and induce expression of T-bet that represses expression of the signature Th17 transcription factor, RAR-related orphan receptor (ROR)γt, and leads to extinction of Il17a and Il17f expression and induction of Ifng expression (11,15,16). Thus, in addition to production of IL-17A and IL-17F, the Th17 pathway can also give rise to "Th1-like" cells that produce IFN-γ.…”

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…1). Additional transcription factors, such as the nuclear receptor 4A (NR4A) family, transcription regulator protein BACH2, RUNX proteins, retinoic acid receptors and aryl hydrocarbon receptor (AHR), clearly have essential roles in the maintenance of polarized states, as the disruption of these transcription factors leads to enhanced plasticity between subsets 43,[121][122][123][124][125] . Nevertheless, even the expression of a suite of transcription factors is not sufficient to drive the transcriptional programmes of T helper cell subsets because access of the transcription factors to their DNA-binding sites in the genome is regulated.…”

“…Indeed, in each of the examples described above, reprogrammed T cells could contribute to mouse models of the human diseases 13,26,71,[167][168][169] . In addition, in mouse models of multiple sclerosis and inflammatory bowel disease, the transition of T H 17 cells to a T H 1 or mixed T H 17/T H 1 cell phenotype is necessary to drive the disease 19,25,122,170,171 . In patients with human T cell leukaemia virus type 1 (HTLV1)-associated myelopathy (also known as tropical spastic para paresis), a neuroinflammatory disorder with multiple sclerosis-like symptoms resulting from infection with HTLV1, the virus is most likely to drive disease by selectively infecting T Reg cells and converting them into IFNγ-producing T H 1-like cells by the direct induction of T-bet expression by virally encoded proteins 172 .…”