Thursday, March 26, 2026
No menu items!
HomeNatureExposed phosphatidylserine is an inhibitory molecule in T cell exhaustion

Exposed phosphatidylserine is an inhibitory molecule in T cell exhaustion

  • 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 Scholar
     

  • Franco, F., Jaccard, A., Romero, P., Yu, Y. R. & Ho, P. C. Metabolic and epigenetic regulation of T-cell exhaustion. Nat. Metab. 2, 1001–1012 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zajac, A. J. et al. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188, 2205–2213 (1998).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leong, Y. A. et al. CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles. Nat. Immunol. 17, 1187–1196 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Beltra, J. C. et al. Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity 52, 825–841.e8 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Utzschneider, D. T. et al. T cell factor 1-expressing memory-like CD8+ T cells sustain the immune response to chronic viral infections. Immunity 45, 415–427 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hudson, W. H. et al. Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1+ stem-like CD8+ T cells during chronic infection. Immunity 51, 1043–1058.e4 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zander, R. et al. CD4+ T cell help is required for the formation of a cytolytic CD8+ T cell subset that protects against chronic infection and cancer. Immunity 51, 1028–1042.e4 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Anderson, A. C., Joller, N. & Kuchroo, V. K. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44, 989–1004 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Birge, R. B. et al. Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death Differ. 23, 962–978 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Segawa, K. & Nagata, S. An apoptotic ‘eat me’ signal: phosphatidylserine exposure. Trends Cell Biol. 25, 639–650 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Arandjelovic, S. & Ravichandran, K. S. Phagocytosis of apoptotic cells in homeostasis. Nat. Immunol. 16, 907–917 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Calianese, D. C. & Birge, R. B. Biology of phosphatidylserine (PS): basic physiology and implications in immunology, infectious disease, and cancer. Cell Commun. Signal. 18, 41 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ran, S., Downes, A. & Thorpe, P. E. Increased exposure of anionic phospholipids on the surface of tumor blood vessels. Cancer Res. 62, 6132–6140 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • Utsugi, T., Schroit, A. J., Connor, J., Bucana, C. D. & Fidler, I. J. Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes. Cancer Res. 51, 3062–3066 (1991).

    CAS 
    PubMed 

    Google Scholar
     

  • Belzile, O. et al. Antibody targeting of phosphatidylserine for the detection and immunotherapy of cancer. Immunotargets Ther. 7, 51–53 (2018).

    Article 

    Google Scholar
     

  • Ran, S. et al. Antitumor effects of a monoclonal antibody that binds anionic phospholipids on the surface of tumor blood vessels in mice. Clin. Cancer Res. 11, 1551–1562 (2005).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Sakuragi, T. & Nagata, S. Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases. Nat. Rev. Mol. Cell Biol. 24, 576–596 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yin, Y., Huang, X., Lynn, K. D. & Thorpe, P. E. Phosphatidylserine-targeting antibody induces M1 macrophage polarization and promotes myeloid-derived suppressor cell differentiation. Cancer Immunol. Res. 1, 256–268 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Budhu, S. et al. Targeting phosphatidylserine enhances the anti-tumor response to tumor-directed radiation therapy in a preclinical model of melanoma. Cell Rep. 34, 108620 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, W. et al. Mobilizing phospholipids on tumor plasma membrane implicates phosphatidylserine externalization blockade for cancer immunotherapy. Cell Rep. 41, 111582 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Phinney, N. Z., Huang, X., Toombs, J. E. & Brekken, R. A. Development of betabodies: the next generation of phosphatidylserine targeting agents. J. Biol. Chem. 300, 107681 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shin, H. W. & Takatsu, H. Phosphatidylserine exposure in living cells. Crit. Rev. Biochem. Mol. Biol. 55, 166–178 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Calianese, D. et al. Phosphatidylserine-targeting monoclonal antibodies exhibit distinct biochemical and cellular effects on anti-CD3/CD28-stimulated T cell IFNγ and TNFα production. J. Immunol. 207, 436–448 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fischer, K. et al. Antigen recognition induces phosphatidylserine exposure on the cell surface of human CD8+ T cells. Blood 108, 4094–4101 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Elliott, J. I. et al. Membrane phosphatidylserine distribution as a non-apoptotic signalling mechanism in lymphocytes. Nat. Cell Biol. 7, 808–816 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hu, Y. et al. Scramblase TMEM16F terminates T cell receptor signaling to restrict T cell exhaustion. J. Exp. Med. 213, 2759–2772 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Suzuki, J. et al. Calcium-dependent phospholipid scramblase activity of TMEM16 protein family members. J. Biol. Chem. 288, 13305–13316 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Carrera Silva, E. A. et al. T cell-derived protein S engages TAM receptor signaling in dendritic cells to control the magnitude of the immune response. Immunity 39, 160–170 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nagata, S., Suzuki, J., Segawa, K. & Fujii, T. Exposure of phosphatidylserine on the cell surface. Cell Death Differ. 23, 952–961 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Segawa, K., Suzuki, J. & Nagata, S. Constitutive exposure of phosphatidylserine on viable cells. Proc. Natl Acad. Sci. USA 108, 19246–19251 (2011).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hu, Y. et al. TGFβ regulates the stem-like state of PD-1+ TCF-1+ virus-specific CD8 T cells during chronic infection. J. Exp. Med. 219, e20211574 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bangs, D. J. et al. CXCR3 regulates stem and proliferative CD8+ T cells during chronic infection by promoting interactions with DCs in splenic bridging channels. Cell Rep. 38, 110266 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Domenjo-Vila, E. et al. XCR1+ DCs are critical for T cell-mediated immunotherapy of chronic viral infections. Cell Rep. 42, 112123 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dahling, S. et al. Type 1 conventional dendritic cells maintain and guide the differentiation of precursors of exhausted T cells in distinct cellular niches. Immunity 55, 656–670.e658 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Wolf, Y., Anderson, A. C. & Kuchroo, V. K. TIM3 comes of age as an inhibitory receptor. Nat. Rev. Immunol. 20, 173–185 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ozga, A. J. et al. CXCL10 chemokine regulates heterogeneity of the CD8+ T cell response and viral set point during chronic infection. Immunity 55, 82–97.e8 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jansen, C. S. et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 576, 465–470 (2019).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, H. et al. AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells. Cell Rep. Med. 3, 100554 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Maier, B. et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 580, 257–262 (2020).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pagliano, O. et al. Tim-3 mediates T cell trogocytosis to limit antitumor immunity. J. Clin. Invest. 132, e152864 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chow, A. et al. Tim-4+ cavity-resident macrophages impair anti-tumor CD8+ T cell immunity. Cancer Cell 39, 973–988.e9 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Espinosa-Carrasco, G. et al. Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors. Cancer Cell 42, 1202–1216.e8 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, J. H. et al. Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy. Nat. Immunol. 25, 644–658 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • He, J., Yin, Y., Luster, T. A., Watkins, L. & Thorpe, P. E. Antiphosphatidylserine antibody combined with irradiation damages tumor blood vessels and induces tumor immunity in a rat model of glioblastoma. Clin. Cancer Res. 15, 6871–6880 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mueller, S. N. et al. PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice. J. Clin. Invest. 120, 2508–2515 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hsiehchen, D. et al. The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial. Nat. Commun. 15, 2178 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sinclair, C. et al. mTOR regulates metabolic adaptation of APCs in the lung and controls the outcome of allergic inflammation. Science 357, 1014–1021 (2017).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Siddiqa, A. et al. A pilot metabolomic study of drug interaction with the immune response to seasonal influenza vaccination. NPJ Vaccines 8, 92 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, S., Siddiqa, A., Thapa, M., Chi, Y. & Zheng, S. Trackable and scalable LC-MS metabolomics data processing using asari. Nat. Commun. 14, 4113 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mitchell, J. M. et al. Common data models to streamline metabolomics processing and annotation, and implementation in a Python pipeline. PLoS Comput. Biol. 20, e1011912 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sud, M. et al. LMSD: LIPID MAPS structure database. Nucleic Acids Res. 35, D527–D532 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • RELATED ARTICLES

    Most Popular

    Recent Comments