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Abstract
CD4+ T cells are the central for the mammalian adaptive immune system. Naïve CD4+ T cells mainly differentiate in to pro-inflammatory Th1, Th2 and Th17 cells upon antigenic stimulation. IFN-γ secreting Th1 cells and IL-17 secreting Th17 cells are found to play key roles in autoimmune diseases like multiple sclerosis (MS) and ulcerative colitis (UC). In this study we found NTG-A-009, 6-aminopyridin-3-ol, has great inhibitory effect on in vitro differentiation of Th1 and Th17 cells without affecting regulatory T cells. Moreover, NTG-A-009 had no effect on CD4+ T cell proliferation and viability. In vivo treatment has shown that NTG-A-009 has ameliorated experimental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS) induced colitis through the inhibition of Th1 and Th17 cells differentiation. Mechanistically, NTG-A-009 suppressed Th1 and Th17 cells differentiation via the modulation of JAK/STAT signaling pathway. Thus, our data demonstrated that NTG-A-009 ameliorated inflammation through the inhibition of Th1 and Th17 cells generation making it a potential therapeutic candidate for the treatment of inflammatory diseases.
Highlights
CD4+ T cells play crucial role in orchestrating adaptive immune response[1] which on activation by T cell receptor get differentiated into specific Th lineages like Th1, Th2, Th17 and regulatory T (Treg) cells depending upon cytokine milieu of the microenvironment[2,3]
In order to assess the effect of this compound on differentiation of T cell, we stimulated naïve CD4+ T cells isolated from spleen and lymph node with anti-CD3 and anti-CD28 in Th differentiation conditions
These findings suggest that CD4+, CD8+ T cells along with the antigen presenting cells (APC) in CNS is critical for the pathogenesis of EAE which was profoundly decreased after NTG-A-009 treatment
Summary
CD4+ T cells play crucial role in orchestrating adaptive immune response[1] which on activation by T cell receptor get differentiated into specific Th lineages like Th1, Th2, Th17 and regulatory T (Treg) cells depending upon cytokine milieu of the microenvironment[2,3]. The Th1 and Th17 cells are important for maintaining the immune response, the abnormal activation and differentiation of Th1 and Th17 cells contribute to multiple autoimmune inflammatory diseases[2,4]. NTG-A-009 treatment was effective in attenuating DSS induced clinical manifestations, histological damage and colon shortening by showing inhibitory effect on pro inflammatory responses of Th1 and Th17 cells. Our findings suggest that NTG-A-009 is relatively safe in terms of cell toxicity and can be used as novel potential therapeutic agent for the treatment of Th1 and Th17 mediated inflammation and autoimmune diseases through the modulation of JAK/STAT signaling pathway
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