Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions

Abstract

Lactate has long been considered a “waste” by-product of cell metabolism, and it accumulates at sites of inflammation. Recent findings have identified lactate as an active metabolite in cell signalling, although its effects on immune cells during inflammation are largely unexplored. Here we ask whether lactate is responsible for T cells remaining entrapped in inflammatory sites, where they perpetuate the chronic inflammatory process. We show that lactate accumulates in the synovia of rheumatoid arthritis patients. Extracellular sodium lactate and lactic acid inhibit the motility of CD4 ⁺ and CD8 ⁺ T cells, respectively. This selective control of T cell motility is mediated via subtype-specific transporters (Slc5a12 and Slc16a1) that we find selectively expressed by CD4 ⁺ and CD8 ⁺ subsets, respectively. We further show both in vitro and in vivo that the sodium lactate-mediated inhibition of CD4 ⁺ T cell motility is due to an interference with glycolysis activated upon engagement of the chemokine receptor CXCR3 with the chemokine CXCL10. In contrast, we find the lactic acid effect on CD8 ⁺ T cell motility to be independent of glycolysis control. In CD4 ⁺ T helper cells, sodium lactate also induces a switch towards the Th17 subset that produces large amounts of the proinflammatory cytokine IL-17, whereas in CD8 ⁺ T cells, lactic acid causes the loss of their cytolytic function. We further show that the expression of lactate transporters correlates with the clinical T cell score in the synovia of rheumatoid arthritis patients. Finally, pharmacological or antibody-mediated blockade of subtype-specific lactate transporters on T cells results in their release from the inflammatory site in an in vivo model of peritonitis. By establishing a novel role of lactate in control of proinflammatory T cell motility and effector functions, our findings provide a potential molecular mechanism for T cell entrapment and functional changes in inflammatory sites that drive chronic inflammation and offer targeted therapeutic interventions for the treatment of chronic inflammatory disorders.

Abstract

High levels of lactate that accumulate in chronic inflammatory sites can trigger unfavorable responses in infiltrating T cells; reducing T cells' sensitivity to lactate might offer therapeutic solutions to chronic inflammatory disorders.

Author Summary

Acidity is a feature of inflammatory sites such as arthritic synovia, atherosclerotic plaques, and tumor microenvironments and results in part from the accumulation of lactate as a product of glycolysis under hypoxic conditions. Recently it has emerged that lactate may be more than just a bystander and might act to modulate the immune-inflammatory response. Here we report just such activity: lactate inhibits T cell motility by interfering with glycolysis that is required for T cells to migrate, it causes T cells to produce higher amounts of the proinflammatory cytokine IL-17, and it triggers loss of cytolytic activity. These phenomena are hallmark features of T cells in chronic inflammatory infiltrates. The functional changes depend on the expression of specific lactate transporters by different subsets of T cells, namely the sodium lactate transporter Slc5a12 in CD4 ⁺ T cells and the lactic acid transporter Slc16a1 in CD8 ⁺ T cells. We propose that T cells entering inflammatory sites sense high concentrations of lactate via their specific transporters. Loss of motility leads to their entrapment at the site, where through their increased production of inflammatory cytokines yet decreased cytolytic capacity, they add detrimentally to chronic inflammation. Targeting lactate transporters and/or metabolic pathways on T cells could deliver novel, invaluable therapeutics for the treatment of widespread chronic inflammatory disorders.