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.

Foxp3+ regulatory T (Treg) cells are broadly divided into naive-like and activated Treg cells, however recent studies suggest further Treg cell heterogeneity. Treg cells contribute to impaired T cell responses in chronic infections, but the role of specific Treg cell subpopulations in viral infections is not well defined. Here, we report that activated Treg cells are separated into two transcriptionally distinct subpopulations characterized by low or high expression of the transcriptional regulator Id3. Id3lo Treg cells are a highly suppressive Treg cell subpopulation, expressing elevated levels of immunomodulatory molecules and are capable of broadly targeting T cell responses. Viral infection and interleukin-2 promote the differentiation of Id3hi into Id3lo Treg cells and during chronic infection Id3lo Treg cells are the predominant Treg cell population. Thus, our report provides a framework, in which different activated Treg cell subpopulations specifically affect immune responses, possibly contributing to T cell dysfunction in chronic infections.