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T lymphocytes, the master regulators of immunity, have an unusual lifestyle. Equipped with a clonally distributed receptor they remain resting for long periods of time but go into overdrive when encountering antigen. Antigen recognition triggers an activation program that results in massive proliferation, differentiation into effector/memory cells, egress from lymphoid storage sites, and production of an array of cytokines. To adapt to the sudden demand for energy and biosynthetic macromolecules, T cells resort to aerobic glycolysis, relying on the Warburg effect to provide sufficient ATP and precursor molecules. Metabolic adaptation to the biosynthetic needs includes upregulation of autophagy, a catabolic process resulting in the degradation of cytoplasmic contents. The close connection between a metabolic switch, proliferative expansion, and functional differentiation connects the metabolic conditions in the cell to normal and pathogenic immunity.
Rheumatoid arthritis (RA) is an autoimmune disease in which T cells are responsible for misdirected immune responses, resulting in tissue inflammation and irreversible damage. In a recent study, RA T cells were found to be metabolically reprogrammed with reduced glucose consumption leading to diminished ATP and lactate production. A loss of the glycolytic activator PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3) was identified as the underlying molecular defect. This bifunctional enzyme controls glycolytic flux by determining the intracellular concentration of fructose-2,6-bisphosphate, an allosteric activator of the glycolytic enzyme, 6-phosphofructo-1-kinase/PFK. Upregulation of PFKFB3 has been implicated in the so-called Warburg effect, a means for tumor cells to fulfill their massive energy needs.
Autophagy can prolong cellular survival in times of energy deprivation. Accordingly, RA T cells could be expected to resort to enhanced autophagic activity. Triggering of the T cell receptor in healthy T cells induces expression of BECN1 and LC3B, preparing the cells for more efficient assembly of the autophagosome. RA T cells fail to upregulate autophagy, contain lower levels of LC3-II and rapidly enter apoptosis in the presence of the autophagy inhibitor 3-MA. Knockin and knockout experiments placed the glycolytic enzyme PFKFB3 upstream of the autophagy machinery.
Metabolic consequences of PFKFB3 deficiency in RA T cells are not limited to weakening of autophagic activity. With reduction of glycolytic flux, RA T cells enhance shunting toward the pentose phosphate pathway and generate increased levels of NADPH. NADPH converts oxidized glutathione, GSSG, to its reduced form, GSH, eventually imposing reductive stress upon the cell. Reduction of cellular ROS stifles the activation-induced boost of H2O2 and superoxide. ROS have been implicated in enhancing autophagy as a survival strategy. Thus, reduced ROS levels may serve as a second mechanism to impair autophagy in RA T cells.
In essence, the regulatory glycolytic enzyme PFKFB3 occupies the top of a regulatory hierarchy, controlling 3 metabolic hotspots in T lymphocytes; utilization of glucose, shunting of glucose-6-phosphate into the pentose phosphate pathway, and regulation of autophagic activity (Fig. 1). Upregulation of the enzyme enables cells to excessively proliferate. Vice versa, deficiency of PFKFB3 renders cells energy deficient and ill-prepared to secure the biosynthetic needs for the biomass enhancement associated with a normal immune response. Aberrations in the autophagy process have been described to be relevant in human disease states. Here, we propose that impaired autophagy has a role in the abnormal T cell differentiation and effector functions that typically occur in RA. The T cell compartment in RA patients undergoes accelerated aging, possibly a consequence of unbalanced T cell loss. Inefficiency in mobilizing the autophagic machinery renders T cells more susceptible to programmed cell death, possibly causing subtle T cell lymphopenia and accelerated T cell turnover. This process could easily speed up T cell aging and lead to premature immunosenescence.
No potential conflicts of interest were disclosed.