Exposed phosphatidylserine is an inhibitory molecule in T cell exhaustion
Summary
This Nature study identifies exposed phosphatidylserine (PS) on the outer leaflet of CD8+ T cells as an active inhibitory signal during T cell exhaustion in chronic viral infection and in human tumours. Using chronic LCMV infection models and human tumour samples, the authors show that PD-1+ exhausted CD8 T cells display elevated external PS despite being viable (not apoptotic). Metabolomic and lipidomic profiling found enriched PS species in exhausted/effector-like subsets. Targeting surface PS with a PS-binding antibody reshaped T cell transcriptional programmes, increased proliferation of stem-like PD-1+TCF1+ cells, altered myeloid and dendritic cell activation, and improved anti-viral responses — effects that could be additive with PD-L1 blockade.
The paper provides supporting bulk RNA-seq and scRNA-seq datasets (GEO accessions GSE310046 and GSE310446) and points to code for metabolomic and lipidomic analyses on GitHub: https://github.com/shuzhao-li-lab/Phosphatidylserine_analyses. The authors include extensive mechanistic, phenotypic and single-cell analyses and validate PS exposure in human renal and lung tumours.
Key Points
- PD-1+ exhausted CD8+ T cells expose phosphatidylserine on their surface while remaining viable — PS exposure is not simply a mark of apoptosis.
- Metabolomic/lipidomic profiling reveals specific PS species are enriched in exhausted and effector-like CD8+ T cell subsets.
- Blocking or targeting surface PS with a PS-binding antibody modulates T cell transcriptional programmes and increases proliferation (Ki67) of stem-like PD-1+TCF1+ cells.
- PS targeting changes myeloid and dendritic cell activation states and antigen-presentation signatures, suggesting cross-talk between PS+ T cells and antigen-presenting cells.
- Combining PS targeting with PD-L1 blockade produced greater improvements in PD-1+ CD8+ T cell responses and viral control than either alone in the chronic LCMV model.
- PS exposure and a PS-metabolism gene signature are detectable in human tumour-infiltrating CD8 T cells (ccRCC and NSCLC), supporting translational relevance for cancer immunotherapy.
- All key datasets are shared (GEO accessions) and analysis scripts for lipidomics/metabolomics are available on GitHub for reproducibility.
Context and relevance
This work links membrane lipid biology — specifically phosphatidylserine externalisation — directly to the inhibitory state of exhausted T cells. It broadens the set of inhibitory signals beyond protein checkpoints (PD-1, TIM3, TIGIT) to a lipid-mediated mechanism that can be targeted therapeutically. For researchers and clinicians working on chronic infection, tumour immunology or next-generation immunotherapies, the finding suggests new combinatorial strategies (PS-targeting agents + checkpoint blockade) and points to lipid metabolism as a functional regulator of T cell fate.
Data and code availability: bulk RNA-seq and scRNA-seq are deposited at GEO (GSE310046, GSE310446) and prior datasets used include PRJNA497086 and GSE140430. Lipidomics/metabolomics scripts: https://github.com/shuzhao-li-lab/Phosphatidylserine_analyses.
Why should I read this?
Short answer: if you care about making exhausted T cells work better — read it. This paper uncovers a surprising, targetable lipid signal on exhausted T cells and shows that messing with PS changes both T cell and dendritic-cell behaviour. It’s neat, practical and potentially actionable for people building immunotherapy combos. We skimmed the dense data for you — the experiments are solid and the translational angle is clear.