Transcription factor Bach2 balances tolerance and immunity - Nature

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Jul 2, 2013 - Immunology and Cell Biology (2013) 91, 491–492; doi:10.1038/icb.2013.32; published online ... CD4 Th cells is determined by several subset-.
Immunology and Cell Biology (2013) 91, 491–492 & 2013 Australasian Society for Immunology Inc. All rights reserved 0818-9641/13 www.nature.com/icb

NEWS AND COMMENTARY Bach2 in control of regulatory T cells

Transcription factor Bach2 balances tolerance and immunity Axel Kallies and Ajithkumar Vasanthakumar Immunology and Cell Biology (2013) 91, 491–492; doi:10.1038/icb.2013.32; published online 2 July 2013

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uring thymic T-cell development, CD4 þ regulatory T cells that express the transcription factor Foxp3 (Tregs) differentiate alongside conventional CD4 þ T cells. While the former restrict the expansion of autoreactive and inflammatory T cells,1 the latter are precursors for specialized populations of CD4 þ T helper (Th) cells that promote immune responses.2 Commitment to a functionally distinct population of CD4 Th cells is determined by several subsetspecific transcription factors. These factors have important roles in setting up Th-specific transcriptional programs and are involved in the suppression of alternate cell fate decisions, a common principle of lineage commitment. This process, although supported by subset-specific transcription factor themselves, also utilizes more widely expressed transcriptional repressors to aid in the stabilization of the lineage.2 A recent paper in Nature by Roychoudhuri et al.3 shows that the transcriptional repressor Bach2 performs such a role by positively regulating Treg development and repressing the effector differentiation programs of conventional CD4 T cells, thereby maintaining the balance between tolerance and immunity. Originally considered a B cell-specific transcription factor, Bach2 deficiency results in poor germinal center formation and antibody class switching.4 A subsequent study on B cells demonstrated that Bach2 suppresses expression of the plasma cell-determining transcription factor Blimp1,5 which consequently leads to elevated plasma cell

A Kallies and A Vasanthakumar are at The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia and The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia E-mail: [email protected]

numbers in Bach2-knockout mice.6 Interestingly, Blimp1 deficiency could rescue class switching in Bach2-deficient B cells, indicating that premature plasma cell differentiation of Bach2-knockout B cells was responsible for their failure to isotype switch.6 In their new and exciting study,3 the authors demonstrate that Bach2-knockout mice develop a slowly progressing wasting disease, which they link to the loss of Treg function and derepression of conventional effector CD4 T cell differentiation. Using RNA and ChIP sequencing to assess the genome-wide functions of Bach2, the authors reveal that Bach2 represses multiple genes associated with CD4 effector T-cell differentiation. Strikingly, Bach2 constrained full differentiation within multiple Th effector populations, including Th1, Th2 and Th17 cells, by directly regulating genes involved in Th polarization and differentiation, such as Irf4, Blimp1, Ahr, Gata3 and Il12r. Moreover, its absence during Tgfbinduced iTreg polarization resulted in an inappropriate diversion to Foxp3  effector cells, and using gain-of-function experiments, the authors convincingly show that this loss of Foxp3 þ cells was a direct consequence of Bach2 deficiency. Interestingly, Bach2 was also required for efficient formation of natural Tregs in the thymus and consequently for the suppression of inflammation in a manner that was Treg cell dependent (Figure 1). Bach2-deficient mice showed a severe reduction of Tregs, which was exacerbated in a competitive situation in bone marrow chimeric mice. Thus, the authors have identified Bach2 a s a factor of striking importance at multiple levels for the control of immune homeostasis. Although this study demonstrates that Bach2 broadly stabilizes immunoregulatory

capacity and represses the differentiation programs of multiple effector lineages in CD4 þ T cells, it also reveals that we are still far from fully understanding how Tregs arise in the thymus and which factors maintain their integrity and function in the periphery. In fact, although several different mechanisms have been identified, it is still unclear precisely how Tregs execute their regulatory function in vivo. In the context of this study, although Foxp3 induction in vitro and Treg numbers in vivo were diminished in the absence of Bach2, stability of Foxp3 in existing Tregs was not affected. Bach2-knockout Tregs were able to suppress T-cell proliferation similar to their wild-type counterparts, and they expressed similar or even higher levels of molecules considered critical for immune regulation, such as CD25, CTLA-4 and GITR. However, despite these features, Bach2-deficient Tregs could not suppress colitis induced by adoptive transfer of naı¨ve T cells into a lymphopenic host, demonstrating that Bach2 has a role in Tregs beyond its requirement for development (Figure 1). One clue may come from the finding that Bach2 regulates the expression of chemokine receptors such as CCR4 and CCR9. Mounting evidence suggests that Tregs can further differentiate into specialized subsets in the periphery in response to diverse inflammatory stimuli. This Treg subset differentiation is dictated by an array of ancillary transcription factors that act in conjunction with Foxp3.7–13 One feature of these Treg subsets is their ability to migrate to distinct tissue locations. Impaired or deregulated expression of chemokine receptors or ancillary transcription factors leads to incorrect tissue localization and localized inflammation. Thus, it is feasible that Bach2 controls peripheral differentiation and function of Tregs at multiple levels.

News and Commentary 492 nTreg FoxP3 Bach2 IL-2

Bach2

iTreg Foxp3 Bach2

FoxP3 Bach2

Bach2

CD4 Bach2

Bach2 CD4 Bach2

Thymus

Irf4 , Bli Ga ta3 mp1, N , Ah r, IL fil3 12R

Periphery

CD4 Th1

CD4 Th2 CD4 Th17

Figure 1 Regulatory T cell fate and CD4 effector T-cell differentiation are linked by Bach2. Bach2 is highly expressed in CD4 single-positive thymocytes. Whereas conventional CD4 T cells appear to develop normally in the absence of Bach2, efficient Treg development in the thymus requires Bach2. After the activation of naı¨ve CD4 T cells in the periphery, Bach2 restricts the development of multiple CD4 effector populations and promotes the differentiation of induced Tregs by directly repressing genes required for Th commitment, such as Irf4, Nfil3, Blimp1, Ahr, Gata3 and Il12r. Tregs themselves require Bach2 for efficient control of T-cell-mediated immune pathology.

Although the requirement for Bach2 for Treg differentiation is clearly demonstrated in the current study, its precise role in this process awaits further study. Repression of the effector program during iTreg differentiation is sufficient to explain deficiencies in the generation of induced Tregs; however, it is unclear how these would impact on Treg generation in the thymus, as repression of the effector differentiation program appears an unlikely requirement at this early phase of Treg development. Thus, it is possible that Bach2 directly has an impact on the thymic selection of Tregs or the induction of Foxp3 itself, and it remains a fascinating subject of further study to illuminate precisely how Bach2 exerts its function during Treg development and influences the function of mature Tregs during immune regulation.

Immunology and Cell Biology

Genetic polymorphisms within the BACH2 locus in humans are associated with susceptibility to numerous autoimmune and allergic diseases including asthma, Crohn’s disease, celiac disease, vitiligo, multiple sclerosis and type 1 diabetes (as in Roychoudhuri et al.3). However, how these polymorphisms impact on disease outcome was unknown. The current study in Nature3 illuminates the functional importance of Bach2 expression in Tregs and conventional CD4 T cells by showing the deleterious effects of tolerance breakdown and inflammatory T-cell expansion in Bach2 /  mice. An independent, very recent study came to similar conclusions, showing that Bach2 restricts expression of effector and memory T cell related genes.14 With these findings Bach2 emerges as a key node in human autoimmunity that clearly justifies more detailed studies to unveil its precise functions.

1 Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012; 30: 531–564. 2 O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4 þ T cells. Science 2010; 327: 1098–1102. 3 Roychoudhuri R, Hirahara K, Mousavi K, Clever D, Klebanoff CA, Bonelli M et al. BACH2 represses effector programs to stabilize Treg-mediated immune homeostasis. Nature 2013; 498: 506–510. 4 Muto A, Tashiro S, Nakajima O, Hoshino H, Takahashi S, Sakoda E et al. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 2004; 429: 566–571. 5 Ochiai K, Katoh Y, Ikura T, Hoshikawa Y, Noda T, Karasuyama H et al. Plasmacytic transcription factor Blimp-1 is repressed by Bach2 in B cells. J Biol Chem 2006; 281: 38226–38234. 6 Muto A, Ochiai K, Kimura Y, Itoh-Nakadai A, Calame KL, Ikebe D et al. Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch. EMBO J 2010; 29: 4048–4061. 7 Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A et al. CD4 þ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 2009; 326: 986–991. 8 Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE et al. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 2012; 486: 549–553. 9 Cretney E, Xin A, Shi W, Minnich M, Masson F, Miasari M et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol 2011; 12: 304–311. 10 Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 2009; 10: 595–602. 11 Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF et al. Foxp3 þ follicular regulatory T cells control the germinal center response. Nat Med 2011; 17: 975–982. 12 Wohlfert EA, Grainger JR, Bouladoux N, Konkel JE, Oldenhove G, Ribeiro CH et al. GATA3 controls Foxp3( þ ) regulatory T cell fate during inflammation in mice. J Clin Invest 2011; 121: 4503–4515. 13 Zheng Y, Chaudhry A, Kas A, deRoos P, Kim JM, Chu TT et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 2009; 458: 351–356. 14 Tsukumo SI, Unno M, Muto A, Takeuchi A, Kometani K, Kurosaki T et al. Bach2 maintains T cells in a naive state by suppressing effector memory-related genes. Proc Natl Acad Sci USA (e-pub ahead of print 10 June 2013).