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Id3 Controls Cell Death of 2B4+ Virus-Specific CD8+ T Cells in Chronic Viral Infection

Sustained Ag persistence in chronic infection results in a deregulated CD8+ T cell response that is characterized by T cell exhaustion and cell death of Ag-specific CD8+ T cells. Yet, the underlying transcriptional mechanisms regulating CD8+ T cell exhaustion and cell death are poorly defined. Using the experimental mouse model of lymphocytic choriomeningitis virus infection, we demonstrate that the transcriptional regulator Id3 controls cell death of virus-specific CD8+ T cells in chronic infection. By comparing acute and chronic infection, we showed that Id3− virus-specific CD8+ T cells were less abundant, whereas the absolute numbers of Id3+ virus-specific CD8+ T cells were equal in chronic and acute infection. Phenotypically, Id3− and Id3+ cells most prominently differed with regard to expression of the surface receptor 2B4; although Id3− cells were 2B4+, almost all Id3+ cells lacked expression of 2B4. Lineage-tracing experiments showed that cells initially expressing Id3 differentiated into Id3−2B4+ cells; in turn, these cells were terminally differentiated and highly susceptible to cell death under conditions of persisting Ag. Enforced Id3 expression specifically increased the persistence of 2B4+ virus-specific CD8+ T cells by decreasing susceptibility to Fas/Fas ligand–mediated cell death. Thus, our findings reveal that the transcriptional regulator Id3 promotes the survival of virus-specific CD8+ T cells in chronic infection and suggest that targeting Id3 might be beneficial for preventing cell death of CD8+ T cells in chronic infection or for promoting cell death of uncontrolled, hyperactive CD8+ T cells to prevent immunopathology.