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.
Highlights
Recent studies have shed light on the interconnection between metabolism and immunity in multicellular organisms and their functional coordination for an effective establishment and resolution of immune responses
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
To assess whether T cell motility is affected by lactate, we performed assays whereby chemotaxis of T cells activated for 5 d with anti-CD3 and anti-CD28 antibodies, and interleukin (IL)2 was induced by the proinflammatory chemokine CXCL10 in the presence of 10 mM lactic acid or sodium lactate, a concentration of lactate we measured in the synovial fluid of rheumatoid arthritis (RA) patients (Fig 1A) and found in a number of inflammatory sites [14,15]
Summary
Recent studies have shed light on the interconnection between metabolism and immunity in multicellular organisms and their functional coordination for an effective establishment and resolution of immune responses. Imbalance of this delicate signaling network might lead to nonresolving inflammation and to the development of chronic inflammatory disease (CID) [1]. The metabolic machinery is likely to directly affect T cell migratory events, as T lymphocytes continuously recirculate between different microenvironments (e.g., blood, lymphoid tissues, and peripheral tissues), which might in turn modulate T cell metabolism In these “milieus”, they are exposed to different nutrient availability and oxygen (O2) tension and must adapt their metabolic pathways to effectively mediate immune responses. The direct effect of metabolism on the trafficking ability of T cells, is yet to be investigated [4]
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