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Blocking of programmed cell death-ligand 1 (PD-L1) expressed on endothelial cells promoted the recruitment of CD8+IFN-γ+ T cells in atherosclerosis

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Abstract

Background

Programmed death ligand-1 (PD-L1) is involved in the negative regulation of immune responses in a variety of diseases. We evaluated the contribution of PD-L1 to the activation of immune cells that promote atherosclerotic lesion formation and inflammation.

Methods and results

Compared to ApoE−/− mice that were provided a high-cholesterol diet in combination with anti-PD-L1 antibody developed a larger lipid burden with more abundant CD8+ T cells. The anti-PD-L1 antibody increased the abundance of CD3+PD-1+, CD8 + PD-1+,CD3+IFN-γ+ and CD8+IFN-γ+ T cell under high-cholesterol diet, as well as the serum tumor necrosis factor-α (TNF-a), IFN-γ, PF, GNLY, Gzms B and LTA. Interestingly, the anti-PD-L1 antibody increased the serum level of sPD-L1. In vitro, blocking of PD-L1 on the surface of mouse aortic endothelial cells with anti-PD-L1 antibody stimulated the activation and secretion of cytokines, including IFN-γ, PF, GNLY, Gzms B and LTA, from cytolytic CD8+IFN-γ+ T cell. However, the concentration of sPD-L1 was lower after treatment of the MAECs with anti-PD-L1 antibody.

Conclusions

Our findings highlighted that blocking of PD-L1 promoted up-regulation of CD8 + IFN-γ + T cell-mediated immune responses, leading to the secretion of inflammatory cytokine that exacerbated the atherosclerotic burden and promoted inflammation. However, further studies are needed to gain insight into whether PD-L1 activation could be a novel immunotherapy strategy for atherosclerosis.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

References

  1. Libby P. The changing landscape of atherosclerosis. Nature. 2021;592(7855):524–33.

    Article  CAS  PubMed  Google Scholar 

  2. Saigusa R, Winkels H, Ley K. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol. 2020;17(7):387–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mushenkova NV, Summerhill VI, Zhang D, Romanenko EB, Grechko AV, Orekhov AN. Current advances in the diagnostic imaging of atherosclerosis: insight into the pathophysiology of vulnerable plaque. Int J Mol Sci. 2020;21(8):2992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ghosh C, Luong G, Sun Y. A snapshot of the PD-1/PD-L1 pathway. J Cancer. 2021;12(9):2735–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gotsman I, Grabie N, Dacosta R, Sukhova G, Sharpe A, Lichtman AH. Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice. J Clin Invest. 2007;117(10):2974–2782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rodig N, Ryan T, Allen JA, Pang H, Grabie N, Chernova T, Greenfield EA, Liang SC, Sharpe AH, Lichtman AH, Freeman GJ. Endothelial expression of PD-L1 and PD-L2 downregulates CD8+ T cell activation and cytolysis. Eur J Immunol. 2003;33(11):3117–26.

    Article  CAS  PubMed  Google Scholar 

  7. Nano E, Petropavlovskaia M, Rosenberg L. Islet neogenesis associated protein (INGAP) protects pancreatic β cells from IL-1β and IFNγ-induced apoptosis. Cell Death Discov. 2021;7(1):56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ait-Oufella H, Libby P, Tedgui A. Anticytokine immune therapy and atherosclerosis cardiovascular risk. Arterioscler Thromb Vasc Biol. 2019;39(8):1510–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kobiyama K, Ley K. Atherosclerosis. Circ Res. 2018;123(10):1118–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shao Y, Saredy J, Yang WY, Sun Y, Lu Y, Saaoud F, Drummer C 4th, Johnson C, Xu K, Jiang X, Wang H, Yang X. Vascular endothelial cells and innate immunity. Arterioscler Thromb Vasc Biol. 2020;40(6):e138–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chandler NJ, Call MJ, Call ME. T cell activation machinery: form and function in natural and engineered immune receptor. Int J Mol Sci. 2020;21(19):7424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, Sasmal DK, Huang J, Kim JM, Mellman I, Vale RD. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017;355:1428–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schwartz DM, Burma AM, Kitakule MM, Luo Y, Mehta NN. T cells in autoimmunity-associated cardiovascular disease. Front Immunol. 2020;11: 588776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 2006;86:515–81.

    Article  CAS  PubMed  Google Scholar 

  15. Wang X, Yang L, Huang F, Zhang Q, Liu S, Ma L, You Z. Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells. Immunol Lett. 2017;184:7–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tsukamoto M, Imai K, Ishimoto T, Komohara Y, Yamashita YI, Nakagawa S, Umezaki N, Yamao T, Kitano Y, Miyata T, Arima K, Okabe H, Baba Y, Chikamoto A, Ishiko T, Hirota M, Baba H. PD-L1 expression enhancement by infiltrating macrophage-derived tumor necrosis factor-α leads to poor pancreatic cancer prognosis. Cancer Sci. 2019;110(1):310–20.

    CAS  PubMed  Google Scholar 

  17. Thiem A, Hesbacher S, Kneitz H, di Primio T, Heppt MV, Hermanns HM, Goebeler M, Meierjohann S, Houben R, Schrama D. IFN-gamma induced PD-L1 expression in melanoma depends on p53 expression. J Exp Clin Cancer Res. 2019;38(1):397.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhu X, Lang J. Soluble PD-1 and PD-L1: predictive and prognostic significance in cancer. Oncotarget. 2017;8:97671–82.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Frigola X, Inman BA, Krco CJ, Liu X, Harrington SM, Bulur PA, Dietz AB, Dong HA, Kwon ED. Soluble B7–H1: differences in production between dendritic cellsand T cells. Immunol Lett. 2012;142:78–82.

    Article  CAS  PubMed  Google Scholar 

  21. Thiem A, Hesbacher S, Kneitz H, di Primio T, Heppt MV, Hermanns HM, Goebeler M, Meierjohann S, Houben R, Schrama D. IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression. J Exp Clin Cancer Res. 2019;38(1):397.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Rodig N, Ryan T, Allen JA, Pang H, Grabie N, Chernova T, Greenfield EA, Liang SC, Sharpe AH, Lichtman AH, Freeman GJ. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur J Immunol. 2003;33:3117–26.

    Article  CAS  PubMed  Google Scholar 

  23. Frebel H, Nindl V, Schuepbach RA, Braunschweiler T, Richter K, Vogel J, Wagner CA, Loffing-Cueni D, Kurrer M, Ludewig B, Annette O. Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice. J Exp Med. 2012;209:2485–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ai L, Xu A, Xu J. Roles of PD-1/PD-L1 pathway: signaling, cancer and beyond. Adv Exp Med Biol. 2020;1248:33–59.

    Article  CAS  PubMed  Google Scholar 

  25. Liu S, Qin T, Liu Z, Wang J, Jia Y, Feng Y, Gao Y, Li K. anlotinib alters tumor immune microenvironment by downregulating PD-L1 expression on vascular endothelial cells. Cell Death Dis. 2020;11:309.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Koga N, Suzuki J, Kosuge H, Haraguchi G, Onai Y, Futamatsu H, Maejima Y, Gotoh R, Saiki H, Tsushima F, Azuma M, Isobe M. Blockade of the interaction between PD-1 and PD-L1 accelerates graft arterial disease in cardiac allografts. Arterioscler Thromb Vasc Biol. 2004;24:2057–62.

    Article  CAS  PubMed  Google Scholar 

  27. Johnson RMG, Wen T, Dong H. Bidirectional signals of PD-L1 in T cells that fraternize with cancer cells. Nat Immunol. 2020;21:365–6.

    Article  PubMed  Google Scholar 

  28. Kak G, Raza M, Tiwari BK. Interferon-gamma (IFN-γ): exploring its implications in infectious disease. Biomol Concepts. 2018;9(1):64–79.

    Article  CAS  PubMed  Google Scholar 

  29. Briscoe J, Guschin D, Rogers NC, Watling D, Muller M, Horn F, et al. JAKs, STATs and signal transduction in response to the interferons and other cytokines. Philos Trans R Soc Lond B Biol Sci. 1996;351:167–71.

    Article  CAS  PubMed  Google Scholar 

  30. Stark GR, Darnell JE Jr. The JAK-STAT pathway at twenty. Immunity. 2012;36:503–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Papi A, Johnston SL. Respiratory epithelial cell expression of vascular cell adhesion molecule-1 and its up-regulation by rhinovirus infection via NF-κB and GATA transcription factors. J Biol Chem. 1999;274:30041–51.

    Article  CAS  PubMed  Google Scholar 

  32. Wan B, Nie H, Liu A, Feng G, He D, Xu R, Zhang Q, Dong C, Zhang JZ. Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis. J Immunol. 2006;177:8844–50.

    Article  CAS  PubMed  Google Scholar 

  33. Sun C, Mezzadra R, Schumacher TN. Regulation and function of the PD-L1 checkpoint. Immunity. 2018;48:434–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China [Grant number 81970382].

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Authors and Affiliations

  1. Department of Pharmacology (State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Baojian Road 157, Harbin, 150086, Heilongjiang, People’s Republic of China

    Simeng Wei, Yue Li, Zhongsha Li, Jingyu Li & Chang Chen

  2. The Biotherapy Center, Tumor Hospital of Harbin Medical University, 150 Haping Road, Harbin, People’s Republic of China

    Qi Li, Fengjiao Wu & Xiaoling Qin

Authors
  1. Qi Li
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  2. Simeng Wei
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  3. Yue Li
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  7. Jingyu Li
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Contributions

Qi LI: Writing-original draft, Funding acquisition. Zhongsha Li: Investigation. Jingyu Li: Investigation. Xiaoling Qin: Formal analysis. Fengjiao Wu: Investigation, Formal analysis. Yu Li: Investigation. Simeng Wei: Investigation. Chang Chen: Writing-review & editing, Supervision.

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Correspondence to Chang Chen.

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Li, Q., Wei, S., Li, Y. et al. Blocking of programmed cell death-ligand 1 (PD-L1) expressed on endothelial cells promoted the recruitment of CD8+IFN-γ+ T cells in atherosclerosis. Inflamm. Res. 72, 783–796 (2023). https://doi.org/10.1007/s00011-023-01703-5

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  • DOI: https://doi.org/10.1007/s00011-023-01703-5

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