T-bet is essential for Th1-mediated, but not Th17-mediated, CNS autoimmune disease.

T cells that produce both IL-17 and IFN-γ, and co-express ROR-γt and T-bet, are often found at sites of autoimmune inflammation. However, it is unknown whether this co-expression of T-bet with ROR-γt is a prerequisite for immunopathology. We show here that T-bet is not required for the development of Th17-driven experimental autoimmune encephalomyelitis (EAE). The disease was not impaired in T-bet(-/-) mice and was associated with low IFN-γ production and elevated IL-17 production among central nervous system (CNS) infiltrating CD4(+) T cells. T-bet(-/-) Th17 cells generated in the presence of IL-6/TGF-β/IL-1 and IL-23 produced GM-CSF and high levels of IL-17 and induced disease upon transfer to naïve mice. Unlike their WT counterparts, these T-bet(-/-) Th17 cells did not exhibit an IL-17→IFN-γ switch upon reencounter with antigen in the CNS, indicating that this functional change is not critical to disease development. In contrast, T-bet was absolutely required for the pathogenicity of myelin-responsive Th1 cells. T-bet-deficient Th1 cells failed to accumulate in the CNS upon transfer, despite being able to produce GM-CSF. Therefore, T-bet is essential for establishing Th1-mediated inflammation but is not required to drive IL-23-induced GM-CSF production, or Th17-mediated autoimmune inflammation.

O'Connor RA ，Cambrook H ，Huettner K ，Anderton SM ... -  《-》

Highly polarized Th17 cells induce EAE via a T-bet independent mechanism.

In the MOG35-55 induced EAE model, autoreactive Th17 cells that accumulate in the central nervous system acquire Th1 characteristics via a T-bet dependent mechanism. It remains to be determined whether Th17 plasticity and encephalitogenicity are causally related to each other. Here, we show that IL-23 polarized T-bet(-/-) Th17 cells are unimpaired in either activation or proliferation, and induce higher quantities of the chemokines RANTES and CXCL2 than WT Th17 cells. Unlike their WT counterparts, T-bet(-/-) Th17 cells retain an IL-17(hi) IFN-γ(neg-lo) cytokine profile following adoptive transfer into syngeneic hosts. This population of highly polarized Th17 effectors is capable of mediating EAE, albeit with a milder clinical course. It has previously been reported that the signature Th1 and Th17 effector cytokines, IFN-γ and IL-17, are dispensable for the development of autoimmune demyelinating disease. The current study demonstrates that the "master regulator" transcription factor, T-bet, is also not universally required for encephalitogenicity. Our results contribute to a growing body of data showing heterogeneity of myelin-reactive T cells and the independent mechanisms they employ to inflict damage to central nervous system tissues, complicating the search for therapeutic targets relevant across the spectrum of individuals with multiple sclerosis.

Grifka-Walk HM ，Lalor SJ ，Segal BM 《-》

Cutting edge: the pathogenicity of IFN-γ-producing Th17 cells is independent of T-bet.

Duhen R ，Glatigny S ，Arbelaez CA ，Blair TC ，Oukka M ，Bettelli E ... -  《-》

Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). The etiology of MS is not well understood, but it is believed that myelin-specific CD4(+) T cells play a central role in initiating and orchestrating CNS inflammation. In this scenario, CD4(+) T cells, activated in the periphery, infiltrate the CNS, where, by secreting cytokines and chemokines, they start an inflammatory cascade. Given the central role of CD4(+) T cells in CNS autoimmunity, they have been studied extensively, principally by using experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the late 1980s, CD4(+) T cells, based on their cytokine production, were divided into two helper lineages, Th1 and Th2 cells. It was postulated that Th1 cells, which produce IFN-γ, mediate inflammation of the CNS in MS/EAE, while Th2 cells, which produce IL-4, have a beneficial effect in disease, because of their antagonistic effect on Th1 cells. The Th1/Th2 paradigm remained the prevailing view of MS/EAE pathogenesis until 2005, when a new lineage, Th17, was discovered. In a relatively short period of time it became apparent that Th17 cells, named after their hallmark cytokine, IL-17A, play a crucial role in many inflammatory diseases, including EAE, and likely in MS as well. The Th17 paradigm developed rapidly, initiating the debate of whether Th1 cells contribute to EAE/MS pathogenesis at all, or if they might even have a protective role due to their antagonistic effects on Th17 cells. Numerous findings support the view that Th17 cells play an essential role in autoimmune CNS inflammation, perhaps mainly in the initial phases of disease. Th1 cells likely contribute to pathogenesis, with their role possibly more pronounced later in disease. Hence, the current view on the role of Th cells in MS/EAE pathogenesis can be called the Th17/Th1 paradigm. It is certain that Th17 cells will continue to be the focus of intense investigation aimed at elucidating the pathogenesis of CNS autoimmunity.

Rostami A ，Ciric B 《-》

Dehydrodiconiferyl alcohol (DHCA) modulates the differentiation of Th17 and Th1 cells and suppresses experimental autoimmune encephalomyelitis.

Dehydrodiconiferyl alcohol (DHCA), originally isolated from the stems of Cucurbita moschata, has previously been shown to exhibit anti-adipogenic and anti-lipogenic effects in 3T3-L1 cells and primary mouse embryonic fibroblasts (MEFs) (Lee et al., 2012). Here, we investigated whether synthetic DHCA could suppress the CD4 T helper 17 (Th17)-mediated production of the interleukin (IL)-17 protein. The results from RT-qPCR suggest that DHCA-mediated down-regulation of IL-17 occurred at the transcriptional level by suppressing the expression of RAR-related orphan receptor (ROR)γt, the master transcription factor involved in the differentiation of Th17 cells. Furthermore, such inhibition was mediated by the suppression of NF-κB activity. DHCA also inhibited the Th1-mediated production of interferon (IFN) γ by controlling the expression of a key transcription factor known to regulate the production of this cytokine, T-bet. In the mouse experimental autoimmune encephalomyelitis (EAE) model, DHCA showed significant therapeutic effects by inhibiting the infiltration of immune cells into the spinal cords, decreasing the differentiation of pathogenic Th17 and Th1 cells, suppressing the expression of various pro-inflammatory cytokines, and eventually ameliorating the clinical symptoms of EAE mice. Taken together, our data indicate that DHCA may be a potential candidate as an agent for the control of Th17 and Th1-mediated inflammatory diseases.

Lee J ，Choi J ，Lee W ，Ko K ，Kim S ... -  《-》