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. 2020 Jun 3;11:1143. doi: 10.3389/fimmu.2020.01143

Figure 2.

Figure 2

Proposed model for the T cell-intrinsic role of IRF5 as a negative regulator of Th2 effector function and differentiation. (1) Antigenic stimulation of the TCR induces the upregulation of IRF4, which acts as a repressor of IRF5 transcription. (2) Stimulation of the IL-4R by IL-4 on naïve CD4+ T cells induces STAT6 activation and nuclear translocation. (3) Phosphorylated STAT6 synergizes with IRF4 to activate GATA3 transcription. (4) A positive regulatory loop supported by GATA3-mediated IRF4 transcription augments Th2 polarization. (5) GATA3 induces permissive chromatin remodeling at the IL4, IL5, and lL13 Th2 cytokine locus. (6) IRF4 inhibits the TLR-induced activation of IRF5 via antagonizing the interaction between MyD88 and IRF5. (7) Nuclear IRF5 functions as a negative regulator of IKZF1 transcription, which limits the production of Ikaros. (8) Ikaros and GATA3 promote the transcription of accessible Th2 polarizing genes including IL4, IL5, and IL13. (9) Ikaros and GATA3 further reinforce the Th2 phenotype via repression of the Th1 transcriptional network.