Editors' ChoiceMetabolism

When T cells lap up lactate

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Science Translational Medicine  20 Nov 2019:
Vol. 11, Issue 519, eaaz9753
DOI: 10.1126/scitranslmed.aaz9753


Lactate drives rheumatoid arthritis progression by altering CD4+ T cell metabolism.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint swelling and chronic inflammation. Swollen joints progressively accumulate various types of immune cells, which secrete deleterious inflammatory cytokines. In addition to immune cell infiltration, enhanced anaerobic catabolism with a consequent lactate accumulation in joints contributes to RA progression. Pucino et al. demonstrated recently that lactate exacerbates damage in RA through metabolic rewiring of T helper 17 (TH17) cells, a subtype of CD4+ T cells known to drive disease progression.

The authors first activated CD4+ T cells isolated from healthy donors in the presence of RA synovial fluid and observed induction in the lactate transporter SLC5A12. They recapitulated this finding by treating activated CD4+ T cells with lactate in a concentration usually found in RA synovial fluid. The consequent influx of lactate enhances the expression of interleukin-17 (IL-17) and its transcriptional regulator, RORγT and ultimately TH17 differentiation. Interestingly, lactate did not affect expression of FOXP3, which drives the differentiation of another subtype of anti-inflammatory CD4+ T cells called regulatory T cells.

To unravel the mechanistic details of lactate-induced TH17 differentiation, the authors first showed that lactate decreased glucose uptake and inhibited glycolysis in activated CD4+ T cells. Since lactate-treated CD4+ T cells maintained their oxygen consumption, the authors hypothesized that CD4+ T cells utilize lactate as alternative nutrient source. To test this hypothesis, they incubated activated CD4+ T cells with labeled lactate and found that lactate carbons contributed to almost 50% of the newly synthesized fatty acids. Interestingly, pharmacological inhibition of key enzymes involved in fatty acid synthesis reduced lactate-induced expression of IL-17, suggesting a role of fatty acid metabolism in lactate-induced TH17 differentiation. Functionally, lactate-induced altered metabolism decreased cell motility, migration, and ability of CD4+ T cells to leave the inflamed tissue. As a promising translational application of this study, the authors showed that SLC5A12 blockade promoted the egress of CD4+ T cell from inflamed tissue in an organ culture model and improved clinical scores in an experimental model of arthritis.

The current investigation has broad implications since accumulation of lactate is a hallmark in other pathological conditions, such as cancer and multiple sclerosis. It is worth exploring whether SLC5A12-dependent scavenging of lactate by CD4+ T cells occurs in cancer. It will be also interesting to test whether SLC5A12 is a promising target in multiple sclerosis. Overall, studying the consequences of metabolic byproducts during progression of various diseases holds great promises for clinical translation.

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