BACH2: The Future of Induced T-Regulatory Cell Therapies

Abstract

BACH2 (BTB Domain and CNC Homolog 2) is a transcription factor that serves as a central regulator of immune cell differentiation and function, particularly in T and B lymphocytes. A picture is emerging that BACH2 may function as a master regulator of cell fate that is exquisitely sensitive to cell activation status. In particular, BACH2 plays a key role in stabilizing the phenotype and suppressive function of transforming growth factor-beta (TGF-β)-derived human forkhead box protein P3 (FOXP3)⁺ inducible regulatory T cells (iTregs), a cell type that holds great clinical potential as a cell therapeutic for diverse inflammatory conditions. As such, BACH2 potentially could be targeted to overcome the instability of the iTreg phenotype and suppressive function that has hampered their clinical application. In this review, we focus on the role of BACH2 in T cell fate and iTreg function and stability. We suggest approaches to modulate BACH2 function that may lead to more stable and efficacious Treg cell therapies.

Keywords: BACH2; FOXP3 stability; T lymphocytes; inducible regulatory T cells.

Figure 1

BACH2 structure and mutations. The domain structure of BACH2 is shown, along with the location and effects of known disease-associated mutations and experimental mutations.

Figure 2

BACH2 regulates T-cell activation. T-cell receptor (TCR) engagement leads to phosphorylation of signaling molecules and the nuclear translocation of BACH2 and other transcription factors that regulate gene expression and T-cell activation. Metabolic status and other inputs regulate BACH2 localization and function. Inhibitors of the different steps of signal transduction pursued to stabilize iTreg phenotype and function are shown. The off-target effects of inhibiting HDACs and other pleiotropic factors raise the need for new, more targeted approaches. BACH2 is central to iTreg stability, regulating transcriptional responses to multiple signaling inputs. The further elucidation of the iTreg-specific roles of BACH2 should enable the identification of more targeted approaches to iTreg stabilization.

Figure 3

BACH2, AP-1 and NFAT consensus recognition sites in FOXP3 promoter. The overlap of BACH2 consensus binding sites with those of AP-1 (indicated by underline) and NFAT1 (indicated in gray) is shown. Competition between BACH2 and these transcription factors for binding sites in the FOXP3 promoter may regulate FOXP3 transcriptional stabilization.

Figure 4

Mechanisms regulating BACH2 function. BACH2 integrates diverse metabolic and signaling inputs and mediates transcriptional responses controlling Treg stability and cell fate.