Pertussis Toxin as well as Staphylococcal superantigen induce glycolysis as the major energy source during CD4+ T cell activation in a human tonsil organoid model

Bystander activation represents an innate-like mechanism by which T cells, particularly effector and memory subsets, can become activated in the absence of cognate antigen recognition. Using human tonsil organoid cultures as a physiologically relevant model, we investigated bystander activation of CD4+ memory T cells in situ in comparison to superantigen stimulation. Tonsillar T cells were stimulated with pertussis toxin – a component of the childhood pertussis vaccine – in comparison to TSST-1 as the staphylococcal superantigen and assessed for activation status, cytokine expression, RNA expression, and metabolic reprogramming. We observed robust T cell activation and cytokine production as well as transcriptional changes comparable to that elicited by TSST-1. Notably, both bystander- and superantigen-activated T memory cells exhibited a metabolic shift toward glycolysis as the dominant energy pathway. These findings demonstrate the similarities of bystander and superantigen-induced TCR -independent T cell activation and show up pathways to sway bystander activation depending on the immunological context.