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. 2021 Apr 26;12:671579. doi: 10.3389/fimmu.2021.671579

Figure 3.

Figure 3

Transcriptional regulation of signaling pathways during Tr1 cell induction. Cytokines, cytokine receptors and transcription factors establish a signaling transduction network to induce Tr1 cells in vitro and in vivo. IL-27 is a key cytokine in these pathways. IL-27 activates c-Maf and AhR. IL-27 along with TCR stimulation also induces high levels of Egr-2 which drives Blimp-1 expression. Conversely, TGF-β signaling antagonizes Blimp-1 by inducing AhR and c-Maf. c-Maf, AhR and Egr-2-Blimp-1 axis promote IL-10 and IL-21 secretion. The autocrine IL-10 and IL-21 maintain Tr1 cell stability via p38 MAPK and STAT3 respectively. Eomes is another key transcription factor. Eomes is dependent on IL-27, and interacts Blimp-1 to activate IL-10 expression. IRF1 and BATF which induced by TCR activation and IL-27 prepare the chromatin landscape for induction of the Tr1 gene network. IL-6 and other STAT3 activating cytokines might utilize the same transcriptional factors to generate Tr1 cells.