3.3 Regulating the Th1/Th2 Immune Balance
In the microenvironment, the proliferation and differentiation of Th1/Th2 cells are affected by various factors such as cytokines, antigen properties, T cell receptor signal intensity, antigen-presenting cell types and costimulatory molecules.67-69 In addition to these external factors, cell redox status is believed to play a role in Th cell differentiation. T cells have limitations in terms of cystine uptake and require exogenous mercaptan for their activation to play a role in this process. During antigen presentation, after dendritic cells interact with T cells, the former generate and release Trx1, which reduces extracellular cystine to cysteine used by T cells; thus, the normal proliferative ability of T cells and an effective immune response is maintained.70,71 Trx1 also controls the redox state of cell surface receptors, such as CD4 and CD30, and thereby affects the behaviour of T cells.72,73 When Th2 cytokine responses are increased, Trx1 induces the expression of Th1-like cytokines, such as IL-1α, IL-1β, IL-1Ra and IL-18, which in turn suppresses Th2-like cytokine expression.22 In recent studies, Trx1 has been confirmed as a specific target gene induced by the cytokine IFN-γ that directly drives the Th1 immune response.74,75Indeed, IFN-γ promotes Th1 differentiation and down-regulates the Th2 response.76 Exogenous Trx1 can induce the expression and release of IFN-γ in Th1 cells, and the increased IFN-γ level in turn increases the Trx1 level. The intracellular Trx1 of IFN-γ-activated macrophages increases the secretion of the Th1 cytokine IL-12 by regulating the thiol redox state. Given the mutual induction and promotion of Trx1 and IFN-γ by immune cells during oxidative stress, a positive feedback mechanism could exist between Trx1 and IFN-γ as they participate in stimulating Th1 immunity.75 Recently, IL-4 has been identified as a new target of Trx1; specifically, its activity can be selectively suppressed by Trx177(Figure 2); thus, the production of IgE by B cells may also be effectively blocked. However, Trx1 does not directly affect the proliferation and differentiation of Th1/Th2 cells; instead, it suppresses inflammation by regulating the production and release of Th1/Th2 cytokines because lymphocytes isolated from Trx1-transgenic (Trx1-Tg) mice are similar to those from WT mice in terms of their ability to produce Th2 cytokines, such as IL-4, IL-5 and IL-13, once they leave an in vivo environment with high Trx1.24 Thus, Trx1 may prevent the occurrence and progression of Th2-driven allergic inflammatory conditions by adjusting the Th1/Th2 balance.