Critical Role of TCF-1 in Repression of the IL-17 Gene

Overwhelming activation of IL-17, a gene involved in inflammation, leads to exaggerated Th17 responses associated with numerous autoimmune conditions, such as experimental autoimmune encephalomyelitis (EAE). Here we show that TCF-1 is a critical factor to repress IL-17 gene locus by chromatin modifications during T cell development. Deletion of TCF-1 resulted in increased IL-17 gene expression both in thymus and peripheral T cells, which led to enhanced Th17 differentiation. As a result, TCF-1-/- mice were susceptible to Th17-dependent EAE induction. Rag1-/- mice reconstituted with TCF-1-/- T cells were also susceptible to EAE, indicating TCF-1 is intrinsically required to repress IL-17. However, expression of wild-type TCF-1 or dominant negative TCF-1 did not interfere with Th17 differentiation in mature T cells. Furthermore, expression of TCF-1 in TCF-1-/- T cells could not restore Th17 differentiation to wild-type levels, indicating that TCF-1 cannot affect IL-17 production at the mature T cell stage. This is also supported by the normal up-regulation or activation in mature TCF-1-/- T cells of factors known to regulate Th17 differentiation, including RORγt and Stat3. We observed hyperacetylation together with trimethylation of Lys-4 at the IL-17 locus in TCF-1-/- thymocytes, two epigenetic modifications indicating an open active state of the gene. Such epigenetic modifications were preserved even when TCF-1-/- T cells migrated out of thymus. Therefore, TCF-1 mediates an active process to repress IL-17 gene expression via epigenetic modifications during T cell development. This TCF-1-mediated repression of IL-17 is critical for peripheral T cells to generate balanced immune responses

Association between branched-chain amino acid intake and physical function among Chinese community-dwelling elderly residents.

This study aimed to evaluate the potential associations of dietary BCAAs (isoleucine, leucine, and valine) with physical function in the elderly Chinese population. A validated semiquantitative food frequency questionnaire and anthropometric and physical function measurements were used to collect data. We modeled trends in physical function indicators for BCAA quartiles using multivariate linear regression models. Among 4336 (43.97% men) participants aged 72.73 ± 5.48 years, a higher dietary intake of BCAAs was positively associated with increased handgrip strength (all p trends < 0.001), shorter times for 4-m fast walking (all p trends < 0.001) and repeated chair rises (all p trends < 0.001). No linear association was found between subtypes of amino acids and any physical functions (all p trends > 0.05). Individuals in the highest quartiles of BCAA intake had a reduced risk of developing low muscle strength, and the multiadjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for women and men were 0.50 (0.38–0.65) and 0.67 (0.50–0.91), respectively. Similarly, higher BCAA consumption was associated with a lower risk of developing low physical performance (4-m walking speed: OR = 0.68 [0.50–0.93]; repeated chair rises: OR = 0.66 [0.54–0.81]). Higher dietary BCAA intake might be beneficial for physical function in the elderly population