By Ben Molloy PhD
Metabolism describes the chemical processes that maintain homeostasis in the cells of living organisms. Commonly it is thought of as “the breakdown” of nutrients to provide “energy”, but this underestimates the inherent complexity between different cell populations and the demands placed on them (Yang et al., 2015).
T-cells and Adaptive Immunity
T-cells are the primary orchestrators of adaptive immunity. Briefly, when dendritic cells encounter a foreign or perceived foreign antigens, they process and present these on MHC II receptors to naïve T-cell populations, which become activated, proliferate and mount a directed immune response against said antigen. Is it reasonable to expect that those naïve or quiescent T-cell populations will have identical metabolic requirements when they become stimulated?There are two principal avenues available to the cell in the generation of ATP – glycolysis or oxidative phosphorylation.
Glucose is actively transported through the cell membrane into the cytosol where glycolysis occurs – the conversion of glucose to pyruvate. Simplistically, the fate of pyruvate largely determines the metabolic signature of T-cell populations. Quiescent and anti-inflammatory T-cells (for instance Treg) have a preference for sustained ATP production (O’Neill and Hardie, 2013) and transport pyruvate to the mitochondria where it is decarboxylated to create acetyl-CoA, the primary substrate for the tricarboxylic acid (TCA) cycle; a series of chemical reactions that generate NADH which is then fed into the electron transport chain leading to the generation of ATP and carbon dioxide.
When maximal ATP production is necessary, cells will adopt oxidative phosphorylation, which produces 36 molecules of ATP per molecule of glucose. Glycolysis is typically favoured under anaerobic conditions, when sufficient oxygen is not available. In the cytosol, pyruvate is converted to lactate by the enzyme lactate dehydrogenase, generating 2 molecules of ATP per molecule of glucose. However, there are instances when a T-cell chooses to adopt glycolysis even when oxygen is plentiful. Why would a T-cell choose to produce less ATP, or the more pertinent question is when does a T-cell choose to do so?
The Warburg Effect
The Warburg Effect, first described in cancerous cells, is a physiological adaptation to the stress placed on a rapidly proliferating cellular population. When T-cells are activated, the primary selective pressure is not the generation of ATP but biomass for the synthesis of signaling mediators and the components necessary for cell replication (Vander Heiden et al., 2009). Lactate is an excellent source of biomass, and therefore, metabolic programs divert from oxidative phosphorylation to aerobic glycolysis. It is an elegant solution to the primary demand made upon pro-inflammatory T-cells. However, given that the adaptation was first recorded in cancer cells, and the crucial function it performs in mounting an effective immune response, the Warburg Effect is susceptible to manipulation, inherited defects or upstream signaling aberrations.
Autoimmunity and T-Cells
In autoimmunity, T-cells become chronically activated, and this chronic activation can have dire consequences for the initiation, propagation and termination of an immune response. In vitro analyses of chronically activated T-cells have identified reduced CD28 expression and epigenetic remodelling at the CD28 promoter (Weng et al., 2009), presumably a method for suppressing or dampening the aberrant activation signal the cell is receiving. These cells were found to be incapable of increasing aerobic glycolysis and rather exhibited an oxidative phenotype. The Warburg response is not a state that T-cells can maintain indefinitely as it places a severe but necessary stress on the metabolism of the cell. For a short period of time ATP is deemed a lesser priority – but this scenario cannot persist indefinitely. Thus, when T-cells are chronically activated, pushing them constantly toward a Warburg phenotype, they are driven to capitulation and resort to oxidative phosphorylation. This sub-optimal oxidative state in which the T-cell is placed has potentially damaging consequences in the production of certain types of radical oxygen species (ROS) (Perl et al., 2004). In essence, the immune system flags the T-cell until it does something remotely within its expectation, even if that means adopting a harmful phenotype.
T-cells and Lipid Metabolism
Lactate is not the only source of biomass available to the activated T-cell. There is an analogous anabolic response in lipid metabolism, where biosynthetic pathways replace fatty acid oxidation (Robichaud et al., 2013). Lipids are necessary for the construction of cell membranes and membrane-associated lipid rafts which function as physical platforms for the propagation of signaling cascades. These lipid raft structures are highly organised, and defects in their construction or composition have been associated with defective T-cell proliferation (Miguel et al., 2011), thought to be a consequence of aberrant T-cell activation. Anomalies of this kind have been previously noted in systemic lupus erythematous (SLE) (McDonald et al., 2014). SLE belongs to the broad group of disorders classified as autoimmune diseases, which all involve a T-cell directed immune response against cells, tissues and organs of the human body.
Anabolism and Autophagy
The association between the aberrant anabolic profiles and autoimmunity doesn’t end with SLE. There is strong evidence for a failure to adopt the Warburg response in the CD4+ T-cells of rheumatoid arthritis (RA) patients. This was recorded alongside a failure of autophagy in these cells (Yang et al., 2013). Autophagy, the internal cytosolic recycling of cellular material is another major source of biomass for the cell. The potential for common metabolic defects in autoimmunity provides an opportunity for treatment, if, and only if the dysregulated metabolic profiles were found to be the origin of dysfunction.