Response:Resistance of naturally occurring regulatory T cells toward oxidative stress: possible link with intracellular catecholamine content and implications for cancer therapy

Response:

Dr Cosentino et al in their letter to the editor discuss our previous report demonstrating increased resistance of regulatory T cells (Tregs) toward oxidative stress¹  in the context of their findings on a catecholamine (CA) dependent inhibitory functional loop in Tregs.²  Their results demonstrate that Tregs contain higher amounts of CA compared with conventional T cells. As CA is a potential source of endogenous oxidative stress, Tregs would require a greater antioxidative capacity, previously demonstrated by us. We appreciate the insightful comments and wish to highlight 2 important associations: first, the emerging role of the neuroimmunologic axis in cancer; and second, the effects of oxidative stress on CA signaling and vice versa.

A large number of studies in diverse tumor models suggest that stress can promote tumor recurrence and metastasis accompanied by impairment of cellular immunity.³  Based on the established immunosuppressive properties of Tregs, several neurotransmitters such as dopamine, epinephrine, norepinephrine, serotonin and substance P, have been tested in this context for their impact on Tregs. Dopamine was shown to mediate a reduction of suppressive activity, adhesive and migratory capacity in Tregs via the dopaminergic D₁-like receptors (D₁ and D₅ receptors).^2,4  Using serum-derived cortisol and metanephrine as the stress surrogates, a recent study on lymphocyte subpopulations in patients after stroke, demonstrated that Tregs were less affected upon hormonal stimuli compared with other T-cell subpopulations.⁵  These observations underlie the complex balance of the effects exerted by CA in the organism. We are therefore in consensus with Cosentino and colleagues that dopaminergic agents as well as β-adrenoreceptor antagonists should be used in targeted therapy approaches.

In their recent publication Cosentino et al demonstrate that despite the expression of D₁-like receptors on conventional T cells, only Tregs are capable of an effective receptor–second messenger coupling resulting in increased intracellular cAMP.²  One potential factor contributing to this phenomenon could be the increased basal levels of intracellular oxidative stress seen in conventional T cells compared with Tregs.¹  Hydrogen peroxide and subsequent lipid peroxidation leads to an uncoupling of the D₁-like receptor/G-protein unit with a loss of signal transduction.⁶  Treatment with antioxidants restored the coupling, indicating the importance of the redox state. It would be of great relevance to evaluate the effects on D₁-like receptor signaling in conventional T cells treated with antioxidants. Furthermore, low doses of dopamine acting on D₁-like receptors is known to decrease the levels of oxidative stress through phospholipase-D (PLD) signaling,⁷  suggesting an additional mechanism potentially contributing to the distinct redox states in Tregs and conventional T cells, as PLD is also regulated by cAMP.

In addition to the therapeutic approach based on dopaminergic signaling as suggested by Cosentino and coworkers, targeting potential key enzymes responsible for the increased antioxidative capacity in Tregs may be a suitable option. A link between antioxidative enzymes and immunosuppression has already been established in mesenchymal stem cells.⁸  Furthermore, there are indications in the murine system that FOXP3, the master regulator of Tregs, may control the expression of important antioxidative molecules like glutaredoxin.⁹  This hypothesis is currently under investigation and endeavors are directed at abrogating the survival advantage of Tregs in an environment with high levels of oxidative stress.