T cells, only outperformed by stem cells, have enormous capacity for proliferative expansion; a prerequisite for the generation of sufficiently sized populations responding to a specific antigen. In the autoimmune disease rheumatoid arthritis (RA), T cells infiltrate into joint tissue, form organized structures and drive tissue-destructive inflammation.  T cell growth places heavy demand on cellular pathways that provide the metabolic precursor molecules for the synthesis of lipids, nucleic acids, proteins, and other macromolecules.

By isolating T cells from patients with RA and comparing them to T cells from healthy age-matched individuals, we have mapped the metabolic landscape in patient-derived T cells. To meet the demand for biosynthetic building blocks, RA T cells redirect their metabolism away from bioenergy production (ATP) to anabolic processes that support biomass production and mitosis.

The shift in bioenergetic strategies has profound functional consequences for RA T cells. In a humanized mouse model, in which we engraft human synovial tissue and reconstitute immunodeficient NSG mice with patient-derived immune cells, we have demonstrated the robust pathogenic potential of metabolically reprogrammed T cells.

In essence, T cells in RA patients have a defect which is unrelated to their antigen specificity; by redirecting glucose from ATP production towards biomass production they diverge their functional behavior and fuel their disease-inducing capabilities.

Our research team is currently defining the molecular abnormalities that lead to the metabolic switch and explore metabolic engineering as a novel therapy in treating tissue inflammation in RA.