Th eJournal of Brief Reviews Immunology T Cell Fates Zipped Up: How the Bach2 Basic Leucine Zipper Transcriptional Repressor Directs T Cell Differentiation and Function x x Martin J. Richer,*,†,1 Mark L. Lang,‡, and Noah S. Butler‡, ,1 Recent data illustrate a key role for the transcriptional and T cells (4). In this review, we discuss our present un- regulator bric-a-brac, tramtrack, and broad complex derstanding of the role of Bach2 in regulating T cell devel- and cap’n’collar homology (Bach)2 in orchestrating opment and homeostasis, as well as the emerging role of Bach2 T cell differentiation and function. Although Bach2 in regulating the differentiation and function of effector and has a well-described role in B cell differentiation, emerg- memory T cells. The potential for Bach2 to regulate various ing data show that Bach2 is a prototypical member of a states of T cell activation, including quiescence and exhaustion, novel class of transcription factors that regulates tran- is also discussed. scriptional activity in T cells at super-enhancers, or regions of high transcriptional activity. Accumulating data dem- Bach2 basics onstrate specific roles for Bach2 in favoring regulatory Bach2 is a member of the Bach family of basic leucine zipper T cell generation, restraining effector T cell differentia- transcription factors (Fig. 1A). The Bach2 gene is located on tion, and potentiating memory T cell development. Ev- human chromosome 6, 6q15 (chromosome 4, 4A4 in mouse), idence suggests that Bach2 regulates various facets of and encodes a 741-aa protein whose functional domains are T cell function by repressing other key transcriptional highly conserved (.94%) in mice and humans (5, 6). Bach2 regulators such as B lymphocyte–induced maturation expression was originally described as being confined to the protein 1. In this review, we examine our present un- B cell lineage and to some neuronal cells that expressed a derstanding of the role of Bach2 in T cell function and neuron-specific splice variant (7). However, Bach2 expression highlight the growing evidence that this transcriptional was later identified in the T cell lineage where it was reported to bind the IL-2 promoter and was required for maintenance repressor functions as a key regulator involved in main- + tenance of T cell quiescence, T cell subset differentia- of IL-2 production by human cord blood CD4 T cells (8). tion, and memory T cell generation. The Journal of The basic leucine zipper transcription factors characteristi- cally form heterodimers through their leucine zippers with the Immunology, 2016, 197: 1009–1015. musculoaponeurotic fibrosarcoma (Maf) family of proteins yielding NF-E2 transcription factors (reviewed in Ref. 9). ignificant progress has been made in identifying and Bach2 forms heterodimers with small Maf proteins, including, delineating the effects of key transcriptional regulators MafF, MafG, and MafK, allowing binding to Maf recog- S that govern the diverse fates of lymphocytic effector nition elements (MAREs) with the consensus sequence subsets. One such regulator is the transcriptional repressor TGCTGA(G/C)TCA(T/C) (7) (Fig. 1B). Bach2 contains a bric-a-brac, tramtrack, and broad complex and cap’n’collar nuclear localization signal in its Zip domain and a nuclear homology (Bach)2. In addition to its well-defined role in export signal at its C terminus. Several factors regulate Bach2 B cell and plasma cell differentiation (recently reviewed in activity and localization (reviewed in Ref. 2), including PI3K Refs. 1–3), Bach2 is emerging as a functionally important signaling in B cells, which leads to phosphorylation of Ser512 regulator of other immune cell types, including macrophages and cytosolic accumulation. Oxidative stress inhibits the activity *Department of Microbiology and Immunology, McGill University, Montreal, Quebec of Allergy and Infectious Diseases Grant AI078993 and by funds from the Presbyterian H3A 2B4, Canada; †Microbiome and Disease Tolerance Centre, McGill University, Health Foundation of Oklahoma City. Montreal, Quebec H3A 2B4, Canada; ‡Department of Microbiology and Immunology, Address correspondence and reprint requests to Dr. Martin J. Richer or Dr. Noah S. Butler, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; and x McGill University, Department of Microbiology and Immunology, 3775 University Graduate Program in Biosciences, University of Oklahoma Health Sciences Center, Street, Room 406, Montreal, QC H3A 2B4, Canada (M.J.R.) or University of Okla- Oklahoma City, OK 73104 homa Health Sciences Center, Department of Microbiology and Immunology, 940 1M.J.R. and N.S.B. contributed equally to this work. Stanton L. Young Boulevard, Oklahoma City, OK 73104 (N.S.B.). E-mail addresses: [email protected] (M.J.R.) or [email protected] (N.S.B.) ORCIDs: 0000-0002-5737-3217 (M.J.R.); 0000-0002-5137-0576 (M.L.L.); 0000- 0002-1429-0796 (N.S.B.). Abbreviations used in this article: Bach, bric-a-brac, tramtrack, and broad complex and cap’n’collar homology; Blimp-1, B lymphocyte–induced maturation protein 1; iTreg, Received for publication May 12, 2016. Accepted for publication June 8, 2016. peripherally induced regulatory T cell; Maf, musculoaponeurotic fibrosarcoma; MARE, M.J.R. is supported by funds from the Canada Foundation for Innovation (John R. Maf recognition element; miRNA, microRNA; PRDM1, PR domain zinc finger protein 1; Evans Leaders Fund) and by National Sciences and Engineering Research Council of ROR, retinoic acid–related orphan receptor; SE, super-enhancer; Treg, regulatory T cell; Canada Grant RGPIN-2016-04713. N.S.B. is supported by National Institutes of Tfh, T follicular helper. Health/National Institute of Allergy and Infectious Diseases Grant AI125446 and Na- tional Institutes of Health/National Institute of General Medical Sciences Grant Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 GM103447. M.L.L. is supported by National Institutes of Health/National Institute www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600847 1010 BRIEF REVIEWS: REGULATION OF T CELLS BY Bach2 to susceptibility to different diseases, but they may have varying importance depending on the immune mechanisms driving pathology. Bach2 regulation of T cell development and homeostasis Originally described as a transcriptional regulator of B cells, it is now well appreciated that a/b T cells also express Bach2 FIGURE 1. Bach2 basics. (A) Schematic representation of Bach2 protein (Fig. 2A). Bach2-encoding mRNA has been detected in thymic structure. Broad complex–tamtrack–bric-a-brac (BTB) region, basic region, and peripheral T-lineage cells (21). Bach2 transcription grad- and leucine zipper are depicted. (B) DNA binding motif for Bach2. ually increases as T cells undergo differentiation and selection in the thymus, with more pronounced increases as T cells reach of the nuclear export signal and thus leads to nuclear the single-positive developmental stage (21). Expression is ad- accumulation. ditionally regulated upon thymic egress, at least in CD8 T cells, Bach2 function has been most extensively investigated in as Bach2 mRNA expression further increases in naive CD8 B cells where it is known to repress expression of B lymphocyte– T cells as they seed the periphery (21). The factors regulating induced maturation protein 1 (Blimp-1), also known as PR the expression of Bach2 in developing and mature T cells re- domain zinc finger protein 1 (PRDM1), by binding to the main poorly defined, but TCR crosslinking via Ag encounter MARE 59 of the prdm1 (Blimp-1) gene (10). Conditional may lead to a reduction in Bach2 expression. Consistent with ablation of Bach2 in the B cell lineage has revealed that Bach2 this, Ag-experienced effector and memory CD4 and CD8 downregulation is essential not only for Blimp-1 de-repression T cells recovered from the periphery express lower levels of and differentiation of B cells into plasma cells, but also for class Bach2 transcripts, compared with their naive counterparts (21). switch recombination leading to IgG1 secretion (11). However, As detailed below, cytokine signaling and other extrinsic factors the fates of B cells are not governed simply by Bach2 re- are likely important for modulating Bach2 expression or ac- pression of Blimp-1. Rather, a complex transcription factor tivity in T cells. Furthermore, the expression of Bach2 is likely network controls memory B cell and plasma cell differenti- to be posttranscriptionally regulated in lymphocytes, as CD4 ation and key molecular events concomitant with differentiation, T cells express lower amounts of Bach2 protein compared including class switch recombination, somatic hypermutation, with B cells, despite similar abundance of Bach2 transcripts and Ig secretion (1, 2). (21). Recent data also established that the epigenetic regulator MENIN promotes Bach2 expression in CD4 T cells via Bach2 in disease maintenance of histone acetylation at the bach2 locus. This The bach2 gene locus is susceptible to modifications that prevents T cell acquisition of a potentially damaging senescence- impact health. Aberrations in the long arm of chromosome 6 associated secretory phenotype, characterized in part by spon- are often associated with B cell malignancies. This includes a taneous proinflammatory cytokine production associated with Bach2–Bcl2LI fusion product detected in a lymphoma line loss of Bach2 expression (22), and further links Bach2 activity to (12). This resulted in enhanced expression of the antiapoptotic the maintenance of T cell homeostasis. Delineating the mech- protein Bcl2LI (also known as Bcl-xL). In another study, anisms that govern Bach2 transcription and posttranscriptional chromosomal rearrangements in an IgH-Myc–positive lym- regulation in T cells as they develop, mature, undergo ho- phoma resulted in fusion of exon 1 of IgHCd on 14q32 to meostatic proliferation, and respond to infection will be critical exon 2 of bach2 (13). The fusion transcript spanned the entire to further elucidate the biological role and function of Bach2 in coding region (exons 2–9) of bach2 and was highly expressed.