Redox regulation of regulatory T-cell differentiation and functions.

The choice between immunity or tolerance is a consequence of T-cell fate determined by T-cell receptor affinity to cognate MHC-peptide complex, costimulatory molecules and cytokines from antigen presenting cells. While activated, effector and memory T-cells provide immunity against antigens, regulatory T-cells play a pivotal non-redundant role in immune tolerance and tissue repair. T-cell differentiation and functions are also well known to be governed by the redox status. Physiological redox status is determined by oxygen concentration, reactive oxygen species levels and antioxidant concentration (vitamin C, glutathione, vitamin E). Cellular redox state influences the levels of oxygen-dependent ten-eleven translocase (TET) demethylase, hypoxia inducible factor-1α (HIF-1α), and metabolic reprogramming which in turn control the epigenetic modification, transcription, translation and post-translational stability of FoxP3, the master regulator of regulatory T-cell induction and maintenance. Redox changes during foetal development, pregnancy, ageing, infections and cancer bolster differentiation for immune tolerance to non-dangerous non-self-antigens. Incidentally, the changes in blood oxygen levels in pregnant women and developing foetus are accompanied by increase in tolerance due to increased frequency of CD4 + CD25 + FoxP3+ regulatory T-cells. Ageing associated oxidative stress and solid tumour associated hypoxia are also associated with an increase in the number and function of regulatory T-cells. This review covers the aspects of redox regulation of differentiation and functions during development, ageing, immunity and stem cell homeostasis. We also propose redox modulation based therapeutic interventions for prevention and treatment of T-cell associated disorders.