Regulation of T Cell Responses by Ionic Salt Signals

Abstract

T helper cell responses are tailored to their respective antigens and adapted to their specific tissue microenvironment. While a great proportion of T cells acquire a resident identity, a significant proportion of T cells continue circulating, thus encountering changing microenvironmental signals during immune surveillance. One signal, which has previously been largely overlooked, is sodium chloride. It has been proposed to have potent effects on T cell responses in the context of autoimmune, allergic and infectious tissue inflammation in mouse models and humans. Sodium chloride is stringently regulated in the blood by the kidneys but displays differential deposition patterns in peripheral tissues. Sodium chloride accumulation might furthermore be regulated by dietary intake and thus by intentional behavior. Together, these results make sodium chloride an interesting but still controversial signal for immune modulation. Its downstream cellular activities represent a potential therapeutic target given its effects on T cell cytokine production. In this review article, we provide an overview and critical evaluation of the impact of this ionic signal on T helper cell polarization and T helper cell effector functions. In addition, the impact of sodium chloride from the tissue microenvironment is assessed for human health and disease and for its therapeutic potential.

Keywords: T cells; allergy; autoimmunity; cytokines; immune regulation; sodium chloride.

Figure 1

Differential distribution of sodium chloride in human organs. The skin can dynamically store sodium chloride, and thus exceed systemic sodium chloride concentrations in the peripheral blood. Dietary salt intake contributes to sodium chloride accumulation in the skin and possibly other peripheral organs. Neutron activation analysis represents a very sensitive method for the quantification of tissue sodium chloride concentrations. Question marks indicate that sodium chloride concentrations in the indicated organs remain to be established.

Figure 2

Sodium chloride promotes the anti-inflammatory Th17 cell identity in steady-state conditions but can also enforce Th17 cell pathogenicity in IL-1β enriched microenvironments.

Figure 3

Sodium chloride compromises the anti-inflammatory function of Treg cells by the upregulation of proinflammatory (IFN-γ, IL-17) and downregulation of anti-inflammatory cytokines (IL-10). Sodium chloride leads to phosphorylation of p38 mitogen-activated protein kinase (MAPK), then activation of NFAT5 followed by the upregulation of SGK-1. Forkhead box O1 (FOXO1) and Forkhead box O3 (FOXO3) stabilize the FOXP3 locus, a process, which is compromised by their SGK-1-induced phosphorylation. This promotes the loss of anti-inflammatory Treg functions paired with proinflammatory cytokine production (IL-17, IFN-γ).