Pertussis toxin as well as staphylococcal superantigen induce glycolysis as energy source during T cell activation in an adenoid 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 the bystander activation of CD4+ memory T cells in situ in comparison with superantigen stimulation. Tonsillar T cells were stimulated with pertussis toxin-a component of the childhood pertussis vaccine-in comparison with toxic shock syndrome toxin-1 (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 those 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 between bystander and superantigen-induced T cell activation and show up pathways to sway bystander activation depending on the immunological context.