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.