BAd-looking or CHarming: The two faces of BACH2

Follicular T helper (Tfh) cells, particularly those within the germinal centers, play a critical role in helping B cells in clonal expansion and affinity maturation (Crotty, 2014). It has been reported that IL-2-STAT5 signaling, an important pathway for promoting T cell survival and proliferation, also suppresses Tfh cell differentiation (Ballesteros-Tato et al., 2012). STAT5 activation induces the expression of the transcription factor Blimp-1, which has an antagonistic effect on the transcription factor Bcl6 in driving Tfh cell differentiation (Johnston et al., 2012; Crotty, 2014). The transcription factor BACH2 was found to suppress Blimp-1 expression in B cells and thus inhibits plasma cell differentiation, yet in T cells, BACH2 paradoxically inhibited Tfh cell differentiation (Ochiai et al., 2006; Lahmann et al., 2019; Zhang et al., 2019). Is Blimp-1 differently regulated by BACH2 in T cells and B cells, or BACH2 has context-dependent functions in regulating Tfh cells?

The study by Hu and his colleagues (Schroeder et al., 2026) has demonstrated that with high-dose antigen stimulation, BACH2 induced by T cell receptor (TCR)–mediated activation inhibits Blimp-1 expression induced by IL-2-STAT5 signaling while allowing IL-2-STAT5–mediated cell proliferation. On the other hand, with low-dose antigen stimulation, BACH2 directly suppresses the expression of CXCR5, the signature chemokine receptor for Tfh cells. Schroeder et al. (2026) also report that the effects of BACH2 on Tfh cell differentiation depend on the route of immunization and location of the immune response, in addition to the antigen dose. In the event when CD25 (the α subunit of the IL-2 receptor complex) expression is strongly induced by TCR activation (by intranasal immunization, in the draining lymph nodes, or with high-dose antigen), BACH2 promotes Tfh cell differentiation by inhibiting STAT5-mediated Blimp-1 induction. However, under the situations when CD25 is barely induced (by intraperitoneal immunization, in the nondraining lymph nodes, or with low-dose antigen), BACH2 inhibits Tfh cell differentiation by suppressing CXCR5 expression. Therefore, BACH2 has a bidirectional role during Tfh cell differentiation.

Previous report indicates that CXCR5⁺ CD4 T cells express low or no CD25 and thus do not respond well to IL-2, which suppresses Tfh cell differentiation (Pepper et al., 2011). The expression of CD25 and CXCR5 is indeed mutually exclusive 3 days after immunization. To assess CD25 and CXCR5 expression at an earlier stage, Schroeder et al. (2026) analyzed antigen-specific cells 2 days after immunization and found that all the CXCR5⁺ CD4 T cells expressed CD25. By day 3, CD25 and CXCR5 expression displayed a mutually exclusive pattern consistent with the previous report. Early co-expression of CD25 and CXCR5 allows cells committed to Tfh cells to respond to IL-2-STAT5 signaling for cell proliferation. Indeed, Schroeder et al. (2026) showed that STAT5 activation is critical for the expansion of both non-Tfh and Tfh cells. Loss of STAT5 signaling reduced total cell numbers of both CXCR5⁻ and CXCR5⁺ population.

Schroeder et al. (2026) further showed that BACH2 inhibits the induction of Blimp-1 by IL-2-STAT5. Blimp-1 is induced gradually in wild-type (WT) CD4 T cells with the highest expression detected 4 days after T cell activation. However, in the absence of BACH2, high Blimp-1 expression was already found 2 days after T cell activation. BACH2 promotes Tfh cell differentiation largely through inhibition of early Blimp-1 induction by IL-2-STAT5 signaling since additional deletion of either STAT5 or Blimp-1 in BACH2-deficient cells restored CXCR5⁺ cell population. BACH2 also suppresses the expression of CD25, through which BACH2 can also indirectly inhibit the expression of Blimp-1 induced by IL-2.

Mechanistically, Schroeder et al. (2026) report that both BACH2 and STAT5 bind to the Prdm1 (gene encoding Blimp-1) locus at multiple cis-regulatory elements. Although these binding sites co-reside in DNA accessible regions, none of these bindings affects DNA accessibility at the Prdm1 locus. Instead, BACH2 regulates histone acetylation at its binding sites possibly by recruiting histone deacetylase 3 and BACH2-deficient cells displayed increased H3K27Ac at the sites where BACH2 binds.

Gene-deficient animal models are often useful to understand the physiological functions of a particular molecule; however, caution needs to be taken when the gene is involved in the development of the cells under investigation. In this study, although Schroeder et al. (2026) used CD4-Cre to delete the Bach2 gene followed by cell transfer to avoid the effects of BACH2 in other cell types, it is possible that BACH2-deficient naive CD4 T cells may already have preexisting defects since BACH2 is expressed by naive CD4 T cells and it has an important role in maintaining cell quiescence. In fact, it has been reported that BACH2-deficient naive CD4 T cells express IL-33Rα (T1/ST2) and they can rapidly produce type 2 T helper (Th2) cytokine upon stimulation (Tsukumo et al., 2013). How this compound effect, especially a possible increase of GATA3 expression in the absence of BACH2, would affect Tfh cell differentiation is not clear. Nevertheless, Schroeder et al. (2026) clearly demonstrated that BACH2 inhibits Blimp-1 expression at an early stage of T cell activation with a striking effect on day 2 after activation both in vitro and in vivo.

Schroeder et al. (2026) also show that BACH2 expression at the protein level is induced 24 h after TCR activation and peaks at 48 h. This is inconsistent with Bach2 mRNA expression, which is found unchanged upon TCR activation in this study or downregulated in previous studies. Interestingly, while a strong TCR signal induces high levels of IL-2 production and CD25 expression, BACH2 protein induction by TCR is negatively correlated with signaling strength. Furthermore, the decrease of BACH2 expression is correlated with the induction of Blimp-1 in WT CD4 T cells. These results indicate a quantitative and dynamic expression of BACH2 protein plays an important role in regulating T cell activation and differentiation.

It is unknown how BACH2 expression at the protein level is regulated by TCR activation. Furthermore, while Schroeder et al. (2026) have shown low dose of antigen stimulation induces higher levels of BACH2 and BACH2 expression peaks at 48 h after activation, how this dynamic expression of BACH2 in response to different doses is regulated at the single-cell level is unclear. While BACH2 can suppress Blimp-1, it has been reported that IL-2-STAT5 signaling possibly through Blimp-1 induction can inhibit BACH2 expression (He et al., 2024). This suggests that the expression of Blimp-1 and BACH2 may also be mutually exclusive. Using a BACH2 reporter mouse strain and/or a BACH2 antibody that works in flow cytometry will help address these important questions. However, given that BACH2 expression at the mRNA level does not correlate with its protein level, caution is needed in using a BACH2 reporter. In addition, it has been reported that BACH2 activity can be regulated posttranslationally. Whether such regulation also contributes to the bidirectional functions of BACH2 during Tfh cell differentiation requires further investigation.

BACH2 functions virtually in all lymphocytes, including B cells, CD4 T effector cells, regulatory T cells (Tregs), CD8 T cells, NK cells, and innate lymphoid cells (Roychoudhuri et al., 2013; Yao et al., 2021). It is likely that BACH2-mediated Blimp-1 repression is conserved among all lymphocyte subsets. This is correlated with the opposing functions of BACH2 and Blimp-1 in lymphocyte dynamics: BACH2 is associated with cell quiescence, stemlike cells, and memory, whereas Blimp-1 is important for activation, differentiation, and effector functions of lymphocyte subsets.

Consistent with its importance in lymphocyte biology, the BACH2 mutation has been found in patients with immunodeficiency and autoimmunity (Afzali et al., 2017). Interestingly, the disease is caused by BACH2 haploinsufficiency and the heterozygous Bach2-deficient mice have abnormal B cell responses and reduced number of Tregs, suggesting the dose of the BACH2 protein is very important. It is also known that low levels of STAT5 activation are sufficient to support cell proliferation, yet Th2 cell differentiation required high levels of STAT5 signaling (Zhu et al., 2003). Given that IL-2-STAT5 is also involved in Tfh cell expansion, it is likely that optimal Tfh cell differentiation and expansion can be achieved by modulating the relative dosage between IL-2-STAT5 and BACH2. It will be interesting to know whether prolonged and/or high levels of BACH2 expression will allow cells to resist the suppression of the Tfh cell fate by high levels of IL-2 stimulation. In addition, it will be important to understand whether modulating the dose of BACH2 at different stages of Tfh cell differentiation will result in different outcomes. This is feasible to test since it has been recently reported that regulating the dose of BACH2 can improve CD8 T cell–mediated immunotherapy by promoting the differentiation of stem-like T cell progenitors (Alli and Youngblood, 2026).

Cell fate determination of a specific lineage often involves an integrated transcriptional regulatory network. For Tfh cell differentiation, in addition to the Bcl6/Blimp-1 axis and BACH2 reported by Schroeder et al. (2026), many other transcription factors such as STAT3, MAF, BATF, TCF-1, Pou2af1, STAT5, T-bet, Foxp1, and Bhlhe40 regulate Tfh cell differentiation and functions (Crotty, 2014; Zhu et al., 2025). While cytokine signaling is essential for regulating the activities of STAT proteins, the expression and functions of many other transcription factors often depend on TCR-mediated cell activation. Future understanding on how dynamic changes in transcriptional regulatory networks quantitatively and temporally control Tfh cell differentiation and functions at the single-cell level during a variety of immune responses will be critical for designing better vaccine strategies.