The sympathetic nervous system modulates CD4+FoxP3+ regulatory T cells via a TGF-β-dependent mechanism

Abstract

CD4(+)FoxP3(+) Tregs are essential mediators of the peripheral immune response to self-antigens. Accordingly, the homeostatic regulation of Treg activity and number would impact on the immune response to both self- and non-self antigens. Because the sympathetic nervous system (SNS) interacts chemically and physically with the central and peripheral immune system and exerts a direct influence on antigen-presenting cells and effector lymphocytes, we have investigated the effect of chemical ablation of the SNS on the number and function of peripheral Treg. Removal of murine peripheral sympathetic innervation by 6-hydroxydopamine induced an increase in splenic and lymph node CD4(+)FoxP3(+) Tregs by a TGF-beta-dependent mechanism. Further, this increase in Tregs coincides with an inhibition of the induction of experimental autoimmune encephalomyelitis. Our results demonstrate that the SNS is an important contributor to the maintenance of peripheral Treg and TGF-beta acts as a bridge between the immune system and the nervous system. Neurological events mediated by the SNS, such as a stress response, may affect the number of T cells that regulate an immune response. Additionally, targeting Tregs via the SNS may be a novel approach to the prevention or treatment of autoimmune diseases.

Ultrasound Modulates the Splenic Neuroimmune Axis in Attenuating AKI

“…produced an 84% decrease in splenic norepinephrine 40 and has been used in numerous studies, contributing to what is now a large body of evidence demonstrating an interaction between the sympathetic nervous system and immune function. [41][42][43] In our studies, splenic denervation via splenic injections of 6-OHDA completely abolished the protective effect of ultrasound in IRI, strongly suggesting that ultrasound reduces IRI in a catecholaminergic-dependent and presumably splenic nerve-dependent manner. The immune modulatory effect of splenic chemical sympathectomy produced by systemic administration of 6-OHDA, increased splenocyte proliferation and cytokine production, was blocked by pretreating animals with desipramine, a norepinephrine reuptake inhibitor that blocks uptake of 6-OHDA into nerve terminals, suggesting that the effects of 6-OHDA were mediated neuronally.…”

Propranolol Attenuates Surgical Stress–Induced Elevation of the Regulatory T Cell Response in Patients Undergoing Radical Mastectomy

“…Indeed, convincing evidence suggests that it is possible for CAs (stress) to affect Tregs in in vivo environment and in ex vivo cultures (22,34,35). The effects of CAs on Tregs are achieved through both indirect and direct mechanisms.…”

“…One in vitro study has shown that NE can decrease or increase hepatocyte production of TGF-b in a dose-dependent manner (36). Bhowmick et al (34) suggested that the number of peripheral Tregs is mediated by sympathetic nervous system signals, and TGF-b acts as a bridge between the sympathetic nervous and immune systems. And TGF-b was decreased in PBMCs by short-term exposure to E at 24 h, whereas it was increased at day 11 in long-term E cultures; a significant increase in the expression of FOXP3 mRNA in cultures subjected to 11 d of E exposure has also been observed (22).…”

Neuroinflammation: Peripheral and Neurogenic Underlying Processes

“…CA can modulate the proliferation and differentiation of immune cells, as well as cytokine production (Flierl et al, 2008;Peng et al, 2004;Torres et al, 2005). In this context, the sympathetic nervous system is also able to modulate the induction of Treg cells (Bhowmick et al, 2009) via a TGF-β-dependent mechanism, thus acting as a bridge between the immune and the nervous systems.…”