Dysfunction of S100A4 + effector memory CD8 + T cells aggravates asthma.

Progressive loss of effector functions, especially IFN-γ secreting capability, in effector memory CD8 + T (CD8 + T EM ) cells plays a crucial role in asthma worsening. However, the mechanisms of CD8 + T EM cell dysfunction remain elusive. Here, we report that S100A4 drives CD8 + T EM cell dysfunction, impairing their protective memory response and promoting asthma worsening in an ovalbumin (OVA)-induced asthmatic murine model. We find that CD8 + T EM cells contain two subsets based on S100A4 expression. S100A4 + subsets exhibit dysfunctional effector phenotypes with increased proliferative capability, whereas S100A4 - subsets retain effector function but are more inclined to apoptosis, giving rise to a dysfunctional CD8 + T EM cell pool. Mechanistically, S100A4 upregulation of mitochondrial metabolism results in a decrease of acetyl-CoA levels, which impair the transcription of effector genes, especially ifn-γ, facilitating cell survival, tolerance, and memory potential. Our findings thus reveal general insights into how S100A4 + CD8 + T EM cells reprogram into dysfunctional and less protective phenotypes to aggravate asthma.