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<p>T cell exhaustion has been implicated in cancer and infectious diseases. In this study, we report a novel mouse model, “MolT-II”, with T cells expressing a transgenic T cell receptor (TCR) specific for a Moloney virus envelope-derived, MHC class II-presented peptide epitope. Characterization of MolT-II CD4 T cells revealed that they are dysfunctional, showing severely impaired effector functions, reduced proliferation and increased baseline expression of co-inhibitory receptors such as PD-1, LAG-3 and CTLA-4, likely due to chronic exposure to a self-antigen. We further show that epitope-specific peptide vaccination combined with immune checkpoint blockade is able to restore the function of MolT-II CD4 T cells in vivo, associated with enhanced tumor control in mice. The MolT-II mouse strain thus represents an in vivo model for reversible CD4 T cell dysfunction, allowing the study of the role of CD4 T cell regulation in cancer, mechanisms underlying CD4 T cell dysfunction and exhaustion, and novel immunomodulatory therapies aiming to rescue dysfunctional T cells.</p>

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Dysfunctional CD4 T cells in an oncovirus-specific TCR-transgenic in vivo model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月18日

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  • Felicia S. Spitzer,
  • Marcel G. M. Camps,
  • Cedrik M. Britten,
  • Sandra Vloemans,
  • Hester J. T. van Zeeburg,
  • Cornelis J. M. Melief,
  • Tsolere Arakelian,
  • Ferry Ossendorp

摘要

T cell exhaustion has been implicated in cancer and infectious diseases. In this study, we report a novel mouse model, “MolT-II”, with T cells expressing a transgenic T cell receptor (TCR) specific for a Moloney virus envelope-derived, MHC class II-presented peptide epitope. Characterization of MolT-II CD4 T cells revealed that they are dysfunctional, showing severely impaired effector functions, reduced proliferation and increased baseline expression of co-inhibitory receptors such as PD-1, LAG-3 and CTLA-4, likely due to chronic exposure to a self-antigen. We further show that epitope-specific peptide vaccination combined with immune checkpoint blockade is able to restore the function of MolT-II CD4 T cells in vivo, associated with enhanced tumor control in mice. The MolT-II mouse strain thus represents an in vivo model for reversible CD4 T cell dysfunction, allowing the study of the role of CD4 T cell regulation in cancer, mechanisms underlying CD4 T cell dysfunction and exhaustion, and novel immunomodulatory therapies aiming to rescue dysfunctional T cells.