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Warburg and coworkers (Warburg O, Posener K, Negelein E. Z Biochem 152: 319, 1924) first reported that cancerous cells switch glucose metabolism from oxidative phosphorylation to aerobic glycolysis, and that this switch is important for their proliferation. Nothing is known about aerobic glycolysis in T cells from asthma. The objective was to study aerobic glycolysis in human asthma and the role of this metabolic pathway in airway hyperreactivity and inflammation in a mouse model of asthma. Human peripheral blood and mouse spleen CD4 T cells were isolated by negative selection. T cell proliferation was measured by thymidine incorporation. Cytokines and serum lactate were measured by ELISA. Mouse airway hyperreactivity to inhaled methacholine was measured by a FlexiVent apparatus. The serum lactate concentration was significantly elevated in clinically stable asthmatic subjects compared with healthy and chronic obstructive pulmonary disease controls, and negatively correlated with forced expiratory volume in 1 s. Proliferating CD4 T cells from human asthma and a mouse model of asthma produced higher amounts of lactate upon stimulation, suggesting a heightened glycolytic activity. Lactate stimulated and inhibited T cell proliferation at low and high concentrations, respectively. Dichloroacetate (DCA), an inhibitor of aerobic glycolysis, inhibited lactate production, proliferation of T cells, and production of IL-5, IL-17, and IFN-γ, but it stimulated production of IL-10 and induction of Foxp3. DCA also inhibited airway inflammation and hyperreactivity in a mouse model of asthma. We conclude that aerobic glycolysis is increased in asthma, which promotes T cell activation. Inhibition of aerobic glycolysis blocks T cell activation and development of asthma.

An emerging concept is that different types of dendritic cells (DCs) initiate different immune outcomes, such as tolerance vs inflammation. In this study, we have characterized the DCs from the lung draining lymph nodes of mice immunized for allergic airway inflammation or tolerance and examined their interactions with CD4+ T cells. The DC population derived from tolerized mice was predominantly CD11c+, B220+, Gr-1+, CD11b−, and MHC class IIlow, which resembled plasmacytoid-type DCs whereas DCs from the inflammatory condition were largely CD11c+, B220−, Gr-1−, CD11b+, and MHC class IIhigh resembling myeloid-type DCs. The DCs from the tolerogenic condition were poor inducers of T cell proliferation. DCs from both conditions induced T cell IL-4 production but the T cells cultured with tolerogenic DCs were unresponsive to IL-4 as indicated by inhibition of STAT6 activation and expression of growth factor-independent 1, which has been recently shown to be important for STAT6-activated Th2 cell expansion. Our data suggest that airway tolerance vs inflammation is determined by the DC phenotype in lung draining lymph nodes.

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CD4 T helper 2 (Th2) cells, with the characteristic interleukin (IL)-4, IL-5, and IL-13 cytokine secretion profile, play an important role in the initiation and perpetuation of allergic airways disease. It is clear from recent studies that CD4+ T cells with distinct cytokine-producing abilities have regulatory functions that limit allergic inflammation. Studies of allergic airway inflammation in mice have identified different types of T regulatory cells (Tregs) that control the disease phenotype. The cytokines associated with the Treg phenotype in mice include both soluble and cell membrane-bound transforming growth factor (TGF)-beta and IL-10. Both contact-dependent mechanisms involving membrane-bound TGF-beta and contact-independent mechanisms involving soluble TGF-beta and IL-10 have been invoked to describe the function of these Tregs. In humans, studies of milk allergy show an association between circulating CD4+CD25+ Tregs and tolerance to the causative allergen, beta-lactoglobulin. The identification of Tregs as suppressors of allergic disease may promote the development of new therapeutic strategies.

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