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.

Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma

“…In contrast to glucose, lactate levels were increased, and other metabolites may also be affected. Elevated lactate can impair T cells (11,35) and may also contribute to T cell metabolic dysfunction. Similarly, PD-1 was elevated on ccRCC CD8 TIL and may impair T cell metabolism.…”

“…While tumor cells can deplete nutrients (10,15,24,34), no decrease in interstitial glucose levels was observed in ccRCC tumors relative to adjacent normal kidney tissue ( Figure 3A). Nevertheless, lactate can inhibit T cell function (11,35) and was increased in ccRCC interstitial fluid. ccRCC CD8 TIL had normal or a trend toward increased expression of glucose transporter Glut1 and hexokinase 2 (HK2) ( Figure 3B).…”

Estrogen protects the blood–brain barrier from inflammation-induced disruption and increased lymphocyte trafficking

“…Murine T cells were isolated from lymph nodes of C57BL/6 WT mice and activated for 3 days in 24 wells plates coated with anti-CD3 (1 μg/ml) and anti-CD28 (5 μg/ml) antibodies (BioLegend), and containing IL-2 (10 ng/ml; PeproTech) as previously described (15).…”

Lactate at the crossroads of metabolism, inflammation, and autoimmunity

“…In this regard, the discovery of leptin, one of the most abundant adipocyte-derived hormones controlling food intake and metabolism, has suggested that an organism's nutritional status can control immune selftolerance [16]. Recently, metabolites, such as succinate, citrate and lactate, all intermediate and end products of metabolic pathways, have been shown to activate signaling, resulting in the modulation of immune functions [17][18][19]. …”

“…Therefore, activated immune and cancer cells relying mainly upon glycolysis need to increase their uptake of glucose to remain viable and functional [22,23]. This selective utilization of glycolysis even in the presence of oxygen is known as "aerobic glycolysis" or the "Warburg Effect" and although it was originally referred only to the peculiar metabolism adopted by rapidly proliferating cancer cells, it has since been observed in specialized immune cells such as lymphocytes and MUs [18,24]. As a consequence of hypoxic or aerobic glycolysis, lactate is produced and accumulates in the extracellular space.…”