Targeting autoimmune-specific metabolic processes

Follicular helper T (T_FH) cells are involved in both the pathogenesis of systemic lupus erythematosus (SLE) and in protective humoral immune responses to pathogens, making these cells a challenge to target therapeutically. Addressing this challenge, the results of a new study show how blocking glucose metabolism can selectively eliminate autoreactive T_FH cells without compromising T cell-dependent responses to immunization or viral infection.

Credit: Springer Nature Limited

Previous investigations have revealed that inhibiting both glucose metabolism and mitochondrial metabolism reverses autoimmune pathology in lupus-prone mice. “In this study, we performed a detailed analysis of the metabolic requirements of T_FH cells from lupus-prone mice as compared with non-autoimmune controls,” says corresponding author Laurence Morel. “Spontaneous autoreactive T_FH cells, but not influenza virus-specific T_FH cells demanded a high level of glucose metabolism.”

Treatment with 2-deoxyglucose (2DG), an inhibitor of glycolysis and, hence, of glucose metabolism, prevented the expansion of T_FH cells in four mouse models of SLE. However, this treatment did not impair T cell-dependent humoral responses to exogenous antigen, nor did it impair influenza virus-mediated induction of antigen-specific T_FH cells. Conversely, inhibition of glutaminolysis with the glutamine analogue 6-diazo-5-oxo-l-norleucine reduced the production of both antigen-specific antibodies and autoantibodies. The results suggest that, unlike the unique requirement for high levels of glucose in autoreactive T_FH cells, all T_FH cells require glutamine. Overall, the findings highlight the qualitative differences in metabolic requirements between autoreactive T_FH cells and pathogen-specific T_FH cells.

blocking glucose metabolism can selectively eliminate autoreactive T_FH cells

“We are now focusing on the mechanisms responsible for the higher glucose requirements of autoreactive T_FH cells, and what metabolites generated from glucose are specifically required,” says Morel. “We plan also to use other pathogens to understand to what extent our results obtained with influenza virus infection and nominal protein immunization can be generalized.”