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Restoring function in exhausted CD8 T cells during chronic viral infection

Author

Listed:
  • Daniel L. Barber

    (Emory University School of Medicine)

  • E. John Wherry

    (The Wistar Institute)

  • David Masopust

    (Emory University School of Medicine)

  • Baogong Zhu

    (Harvard Medical School)

  • James P. Allison

    (Memorial Sloan-Kettering Cancer Center)

  • Arlene H. Sharpe

    (Harvard Medical School and Brigham and Women's Hospital)

  • Gordon J. Freeman

    (Harvard Medical School)

  • Rafi Ahmed

    (Emory University School of Medicine)

Abstract

Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analysed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the ‘helpless’ CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections.

Suggested Citation

  • Daniel L. Barber & E. John Wherry & David Masopust & Baogong Zhu & James P. Allison & Arlene H. Sharpe & Gordon J. Freeman & Rafi Ahmed, 2006. "Restoring function in exhausted CD8 T cells during chronic viral infection," Nature, Nature, vol. 439(7077), pages 682-687, February.
  • Handle: RePEc:nat:nature:v:439:y:2006:i:7077:d:10.1038_nature04444
    DOI: 10.1038/nature04444
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    Cited by:

    1. Wenji Piao & Lushen Li & Vikas Saxena & Jegan Iyyathurai & Ram Lakhan & Yigang Zhang & Isadora Tadeval Lape & Christina Paluskievicz & Keli L. Hippen & Young Lee & Emma Silverman & Marina W. Shirkey &, 2022. "PD-L1 signaling selectively regulates T cell lymphatic transendothelial migration," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Moujtaba Y. Kasmani & Paytsar Topchyan & Ashley K. Brown & Ryan J. Brown & Xiaopeng Wu & Yao Chen & Achia Khatun & Donia Alson & Yue Wu & Robert Burns & Chien-Wei Lin & Matthew R. Kudek & Jie Sun & We, 2023. "A spatial sequencing atlas of age-induced changes in the lung during influenza infection," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Stefanie Hiltbrunner & Lena Cords & Sabrina Kasser & Sandra N. Freiberger & Susanne Kreutzer & Nora C. Toussaint & Linda Grob & Isabelle Opitz & Michael Messerli & Martin Zoche & Alex Soltermann & Mar, 2023. "Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Kaitao Li & Paul Cardenas-Lizana & Jintian Lyu & Anna V. Kellner & Menglan Li & Peiwen Cong & Valencia E. Watson & Zhou Yuan & Eunseon Ahn & Larissa Doudy & Zhenhai Li & Khalid Salaita & Rafi Ahmed & , 2024. "Mechanical force regulates ligand binding and function of PD-1," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Solhwi Lee & Kunhee Lee & Hyeonjin Bae & Kyungmin Lee & Junghwa Lee & Junhui Ma & Ye Ji Lee & Bo Ryeong Lee & Woong-Yang Park & Se Jin Im, 2023. "Defining a TCF1-expressing progenitor allogeneic CD8+ T cell subset in acute graft-versus-host disease," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Jacqueline A. Turner & Malia A. Fredrickson & Marc D’Antonio & Elizabeth Katsnelson & Morgan MacBeth & Robert Gulick & Tugs-Saikhan Chimed & Martin McCarter & Angelo D’Alessandro & William A. Robinson, 2023. "Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Chen Wang & Changfu Hao & Kai Dai & Yuzheng Li & Jie Jiao & Zhuoya Niu & Xiao Xu & Xuedan Deng & Jing He & Wu Yao, 2022. "Occupational Low-Dose Radiation Affects the Expression of Immune Checkpoint of Medical Radiologists," IJERPH, MDPI, vol. 19(12), pages 1-14, June.
    8. Victor Garcia & Kirsten Richter & Frederik Graw & Annette Oxenius & Roland R Regoes, 2015. "Estimating the In Vivo Killing Efficacy of Cytotoxic T Lymphocytes across Different Peptide-MHC Complex Densities," PLOS Computational Biology, Public Library of Science, vol. 11(5), pages 1-19, May.
    9. Iwami, Shingo & Nakaoka, Shinji & Takeuchi, Yasuhiro, 2008. "Viral diversity limits immune diversity in asymptomatic phase of HIV infection," Theoretical Population Biology, Elsevier, vol. 73(3), pages 332-341.
    10. Emily N. Neubert & Julia M. DeRogatis & Sloan A. Lewis & Karla M. Viramontes & Pedro Ortega & Monique L. Henriquez & Rémi Buisson & Ilhem Messaoudi & Roberto Tinoco, 2023. "HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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