Metabolic rewiring: a new master of Th17 cell plasticity and heterogeneity

Abstract

T helper type 17 (Th17) cells are characterized by inherent plasticity and heterogeneity displaying both pathogenic and tissue-protective functions. Emerging evidence has illuminated a pivotal role for metabolic reprogramming in shaping Th17 cell fate determination. Metabolic responses are regulated by a constellation of factors and environmental triggers, including cytokines, nutrients, oxygen levels, and metabolites. Dysregulation of metabolic pathways not only influences Th17 cell plasticity and effector function but also affects the outcome of Th17-linked autoimmune, inflammatory, and antitumor responses. Understanding the molecular mechanisms underpinning metabolic reprogramming can allow the enhancement of protective Th17 cell-mediated responses during infections and cancer, concomitant with the suppression of detrimental Th17 processes during autoimmune and inflammatory diseases. In the present review, we describe major metabolic pathways underlying the differentiation of Th17 cells and their crosstalk with intracellular signaling mediators, we discuss how metabolic reprogramming affects Th17 cell plasticity and functions, and, finally, we outline current advances in the exploitation of metabolic checkpoints for the development of novel therapeutic interventions for the management of tissue inflammation, autoimmune disorders, and cancer.

Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer

“…Glutamine metabolism has a pivotal role in Th17 cell generation and cytokine (IL-17) secretion. [18,22] In Th17 cells (Figure 9B), glutamine metabolism was similarly downregulated in the JHU083 treatment group, which is in accordance with the robust reduction in Th17 lineage in JHU083-treated mice. GLS inhibition may also limit the protumor IL-17 secretion, which further potentiates the anti-tumor effects of JHU083.…”

Standard Doses of Cholecalciferol Reduce Glucose and Increase Glutamine in Obesity-Related Hypertension: Results of a Randomized Trial

“…In T-cell subsets, for example, which are highly dependent on glucose and glutamine, these changes may induce reshaping and changes in the pattern of activation and cytokine secretion. In the case of short-lived Th17 cells that mostly rely on aerobic glycolysis and glutaminolysis for ATP production [ 39 ], increased glutamine may be responsible for Th17 cell stability and the modulation of reactive oxygen species synthesis and oxidative stress [ 39 ]. Although our trial was not designed to evaluate specific metabolic pathways or, specifically, the uptake of glutamine at the cellular level, we previously documented a restrictive effect of cholecalciferol on Th17 cell expansion in obese hypertensives [ 22 ].…”

Vaccination inducing durable and robust antigen-specific Th1/Th17 immune responses contributes to prophylactic protection against Mycobacterium avium infection but is ineffective as an adjunct to antibiotic treatment in chronic disease

“…Forth, although we demonstrated a role for Th1/Th17 cells induced by GLA-SE/CDG in vaccine-induced protective immunity against Mav-PI in the preventative setting, the precise mechanisms of Th17 responses in the generation of optimal anti-Mav immunity are still unknown. Finally, Th17 cells are identified by unique plasticity and heterogeneity and exert both pathogenic and preventative effects against Mav infection [ 93 , 94 ]. Although we defined Th17 responses using identical markers in preventative and therapeutic immunization, Th17 cells may have heterogeneous plasticity and play different roles in early protection or chronic lung inflammation.…”