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The transcription factors E2 A and HEB (members of the E protein family) have been shown to play essential roles in lymphocyte development, while their negative regulators, the Id proteins, have been implicated in both lymphocyte development and in the CD8+ T-cell immune response. Here, we show that E proteins also influence CD8+ T cells responding to infection. E protein expression was upregulated by CD8+ T cells during the early stages of infection and increased E protein DNA-binding activity could be detected upon TCR stimulation. Deficiency in the E proteins, E2 A and HEB, led to increased frequency of terminally differentiated effector KLRG1hi CD8+ T cells in mice during infection, and decreased generation of longer-lived memory-precursor cells during the immune response. These data suggest a model whereby E protein transcription factor activity favors rapid memory-precursor T-cell formation while their negative regulators, Id2 and Id3, are both required for robust effector CD8+ T-cell response during infection. [ABSTRACT FROM AUTHOR]

During infection, naive CD8+ T cells differentiate into effector cells, which are armed to eliminate pathogens, and memory cells, which are poised to protect against reinfection. The transcriptional program that regulates terminal differentiation into short-lived effector-memory versus long-lived memory cells is not clearly defined. Through the use of mice expressing reporters for the DNA-binding inhibitors Id2 and Id3, we identified Id3hi precursors of long-lived memory cells before the peak of T cell population expansion or upregulation of cell-surface receptors that indicate memory potential. Deficiency in Id2 or Id3 resulted in loss of distinct CD8+ effector and memory populations, which demonstrated unique roles for these inhibitors of E-protein transcription factors. Furthermore, cytokines altered the expression of Id2 and Id3 differently, which provides insight into how external cues influence gene expression. [ABSTRACT FROM AUTHOR]