Dysfunction of S100A4 <sup>+</sup> effector memory CD8 <sup>+</sup> T cells aggravates asthma
Huilei Zhang, Shuangqing Liu, Yanan Li, Jianru Li, Ni Chen, Ming Yang, Jun Dong, Zhaoqing Wang, Zhihai Qin
Abstract
Abstract 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.