The Critical Role of Bach2 in Shaping the Balance between CD4⁺ T Cell Subsets in Immune-Mediated Diseases

Figure 1

Effect of transcription factor Bach2 on CD4⁺ T cell subsets. (1) Bach2 inhibits Th1 cell differentiation. Bach2 inhibits some genes such as IL12RB1 (IL-12Rβ1), IL12RB2, MAP3K8, and GADD45G, which are essential for Th1 cell differentiation, and then inhibits the differentiation of Th1. (2) Bach2 inhibits Th2 cell differentiation and function. Bach2 binds to Batf, and the Bach2-Batf complex restrains the differentiation of Th2 by two pathways. The Bach2-Batf complex directly binds to the AP-1 motif in the regulatory region of the Th2 cytokine locus and inhibits the production of Th2 cytokines. The Bach2-Batf complex also binds to Batf and Batf3 loci to inhibit their transcription, while Batf3 regulates Th2 function. In Bach2^-/- naive CD4⁺ T cells, IL-4 and Batf-Irf4 complex form a positive feedback amplification loop that induces Th2 differentiation. In T cell-specific Bach2^-/- mice, the expression level of Th2 cytokines was elevated, and in the lung cells, the number of pathogenic Th2 cells (IL-33Rα⁺CD4⁺ T cells) with high cytokine expression also increased. (3) Bach2 promotes Th9-associated cytokine secretion. Bach2 promotes IL-9 production in Th9 cells by directly binding to the Il9 gene and by indirectly upregulating the expression of IL-9-inducing transcription factor, such as Batf, Irf4, Junb, and Jun. (4) Bach2 inhibits Th17 differentiation. S100A is a direct target of Bach2. S100A strengthens the severity of inflammatory and Th17 differentiation. Bach2 inhibits Th17 differentiation through binding to S100A. In Bach2^-/- mice, the naive T cells were more likely to differentiate into Th17 cells. (5) Bach2 inhibits Tfh differentiation. Bach2 displaces the complex of Irf-4 and Batf that activates Bcl-6 promoter. Bach2 is also suppressed by Bcl-6 in turn. Bach2 directly downregulates the transcription of Cxcr5, the chemokine receptor of Tfh. (6) Bach2 promotes Treg differentiation. Bach2-inhibited transcription factor Blimp-1 can limit CD4⁺ T cell differentiation into Treg cells. In addition to that, many effector-related genes that Bach2 inhibited can encode signaling proteins that antagonize Treg cell differentiation, including IL12RB1, IL12RB2, and TNFSF4. Moreover, Bach2 plays an indispensable role in the homeostasis maintenance and function of Treg cells. And Bach2 is required for the complete expression of Foxp3, in which Treg cells’ immunomodulatory effects depend on.