Dysfunction of S100A4+ effector memory CD8+ T cells aggravates asthma. Issue 6 (15th April 2022)

• Record Type: Journal Article
• Authors: Zhang, Huilei; Liu, Shuangqing; Li, Yanan; Li, Jianru; Ni, Chen; Yang, Ming; Dong, Jun; Wang, Zhaoqing; Qin, Zhihai
• Is Part Of: European journal of immunology. Volume 52:Issue 6(2022)
• Page Start: 978
• Page End: 993
• Publication Date: 2022-04-15
• Subjects: S100A4 -- effector memory CD8+ T cells -- IFN‐γ -- dysfunction -- allergic asthma; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.202149572
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: Progressive loss of effector functions, especially IFN‐γ secreting capability, in effector memory CD8 + T (CD8 + TEM ) cells plays a crucial role in asthma worsening. However, the mechanisms of CD8 + TEM cell dysfunction remain elusive. Here, we report that S100A4 drives CD8 + TEM cell dysfunction, impairing their protective memory response and promoting asthma worsening in an ovalbumin (OVA)‐induced asthmatic murine model. We find that CD8 + TEM 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 + TEM 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 + TEM cells reprogram into dysfunctional and less protective phenotypes to aggravate asthma. Abstract : Dysfunction of CD8 + TEM cells, especially impaired IFN‐γ secreting capability, is associated with asthma worsening. S100A4 drives dysfunction and proliferation of S100A4 + CD8 + TEM cells by upregulation of mitochondrial metabolism, whereas functional S100A4 − subsets are more inclined to apoptosis, giving rise to a dysfunctional CD8 + TEM cell pool to aggravate asthma.