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

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.