Exposed phosphatidylserine is an inhibitory molecule in T cell exhaustion | Nature
Subjects
- CD8-positive T cells
- Translational immunology
- Viral infection
Abstract
In cancer and chronic infection, CD8 T cell exhaustion is hallmarked by expression of inhibitory receptors such as PD1, TIM3, LAG3 and others1,2,3. Thus, inhibitory molecule focus has been limited to cell-surface proteins. Here we evaluate the surface lipid metabolite phosphatidylserine (PS) as a regulator of exhaustion. PS primarily localizes to the inner plasma membrane of live cells but is well known to be externalized to the outer membrane during cell death. The role of exposed PS on live immune cells is less clear. We show that viable, antigen-specific CD8 T cells externalize PS during lymphocytic choriomeningitis virus (LCMV) infection. T cell activation induced initial PS exposure, and chronic antigen stimulation sustained externalization. Transcriptomic and lipidomic analyses also identified PS accumulation in exhausted CD8 T cells. To evaluate a role for exposed PS in exhaustion, we treated LCMV chronically infected mice with a PS-targeting antibody (mch1N11)4 and found that it expanded LCMV-specific CD8 responses. PD1+TCF1+ stem-like CD8 T cells downregulated quiescence-associated gene modules and increased proliferation after antibody treatment, highlighting an inhibitory role for PS. Mechanistically, exposed PS on T cells functioned extrinsically to suppress dendritic cell immunostimulatory phenotypes, in turn limiting CD8 T cell responses. PS-targeting antibody with anti-PDL1 synergized to increase CD8 responses and improve viral control. Finally, we show that PD1+ CD8 T cells from human tumours can also expose PS. In summary, we detail CD8 T cell PS biology and provide insight into a mechanism by which exposed PS functions as a ‘non-classical’ extrinsic inhibitory molecule in exhaustion.
Access through your institution
Buy or subscribe
This is a preview of subscription content, access via your institution
Access options
Access through your institution
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$32.99 / 30 days
cancel any time
Learn more
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Learn more
Buy this article
- Purchase on SpringerLink
- Instant access to the full article PDF.
USD 39.95
Prices may be subject to local taxes which are calculated during checkout
Fig. 1: Antigen-specific CD8 T cells expose PS.
Fig. 2: PS-targeting antibody increases virus-specific PD1+ CD8 T cell responses.
Fig. 3: PS regulates self-renewal and differentiation of PD1+TCF1+ stem-like CD8 T cells.
Fig. 4: Targeting exposed PS stimulates the antigen-presenting capacity of CD11c+ DCs.
Fig. 5: PS-targeting antibody synergizes with PD1–PDL1 blockade during chronic infection.
Fig. 6: PS exposure is conserved on PD1+ CD8 T cells in human cancer.
Data availability
The following previously published RNA-seq data were used for this study: NCBI BioProject PRJNA497086 and NCBI Gene Expression Omnibus (GEO) GSE140430. Datasets generated in this article are available on the GEO database under the corresponding accessions: bulk RNA-seq (GSE310046) and scRNA-seq (GSE310446). Source data are provided with this paper.
Code availability
Code for RNA-seq and scRNA-seq is available from the corresponding author on reasonable request. All scripts used for metabolomics and lipidomics data preprocessing and relevant analyses are available in a GitHub repository (https://github.com/shuzhao-li-lab/Phosphatidylserine_analyses).
References
- Pauken, K. E. & Wherry, E. J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 36, 265–276 (2015).
Article
CAS
PubMed
PubMed Central
Google Scholar
- Virgin, H. W., Wherry, E. J. & Ahmed, R. Redefining chronic viral infection. Cell 138, 30–50 (2009).
Article
CAS
PubMed
Google Scholar
- McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37, 457–495 (2019).
Article
CAS
PubMed
Google Scholar
- Gray, M. J. et al. Phosphatidylserine-targeting antibodies augment the anti-tumorigenic activity of anti-PD-1 therapy by enhancing immune activation and downregulating pro-oncogenic factors induced by T-cell checkpoint inhibition in murine triple-negative breast cancers. Breast Cancer Res. 18, 50 (2016).
Article
PubMed
PubMed Central
Google Scholar
- Gallimore, A. et al. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J. Exp. Med. 187, 1383–1393 (1998).
Article
CAS
PubMed
PubMed Central
Google Scholar
- Seo, W., Jerin, C. & Nishikawa, H. Transcriptional regulatory network for the establishment of CD8+ T cell exhaustion. Exp. Mol. Med. 53, 202–209 (2021).
Article
CAS
PubMed
PubMed Central
Google Scho