A molecular threshold for effector CD8+ T cell differentiation controlled by transcription factors Blimp-1 and T-bet

Abstract

T cell responses are guided by cytokines that induce transcriptional regulators, which ultimately control differentiation of effector and memory T cells. However, it is unknown how the activities of these molecular regulators are coordinated and integrated during the differentiation process. Using genetic approaches and transcriptional profiling of antigen-specific CD8+ T cells, we reveal a common program of effector differentiation that is regulated by IL-2 and IL-12 signaling and the combined activities of the transcriptional regulators Blimp-1 and T-bet. The loss of both T-bet and Blimp-1 leads to abrogated cytotoxic function and ectopic IL-17 production in CD8+ T cells. Overall, our data reveal two major overlapping pathways of effector differentiation governed by the availability of Blimp-1 and T-bet and suggest a model for cytokine-induced transcriptional changes that combine, quantitatively and qualitatively, to promote robust effector CD8+ T cell differentiation.

Eomesodermin promotes the development of type 1 regulatory T (T R 1) cells

“…Downstream of IL-27, Blimp-1 is critical for the expression of IL-10 in CD4 + T cells in various models (6–8, 21, 49). Here we show Eomes + T R 1 cells were regulated by both Blimp-1 and T-bet, consistent with a recent report that demonstrated close collaboration between Blimp-1 and T-bet in CTL generation (50). In addition, binding of Blimp-1 to the Eomes promoter in CD8 + T cells during viral infection has been described (32), suggesting that Blimp-1 not only regulates IL-10 expression directly but also contributes to the induction or maintenance of Eomes expression in T R 1 cells.…”

Regulation of Memory CD8+ T Cell Differentiation by MicroRNAs

“…To explore further the effects of miRNAs on the expression of these transcription factors, miRNA knockout in T cells has been studied extensively. For example, miR-17-92 deficiency in CD8 + T cells reduces the expression of EOMES, but increases the expression of TBX21, leading to the formation of CD127 lo KLRG-1 hi SLECs [63]. Additionally, miR-139 and miR-342 target and inhibit the expression of EOMES in effector cells [28], which is in keeping with the hypothesis that EOMES is a contributor to the formation of memory precursor cells [59].…”

What Scales the T Cell Response?

“…Scaled accumulation of crucial transcriptional intermediates in proportion to the duration of digital TCR signaling then programs the T cell response. Although not discussed in this article, we note that the same transcription factors and cytokines that program clonal expansion and effector molecule expression also diminish the memory potential of the differentiating T cells [2,33,35,81]. Numerous feedforward interactions in the transcriptional program allow decoding of the duration of signaling, and permit increasing and extending the response well beyond the cessation of signaling[ 2 5 _ T D $ D I F F ] (see Outstanding Questions).…”