The BTB-ZF Family of Transcription Factors: Key Regulators of Lineage Commitment and Effector Function Development in the Immune System This information is current as of October 2, 2021. Aimee M. Beaulieu and Derek B. Sant'Angelo J Immunol 2011; 187:2841-2847; ; doi: 10.4049/jimmunol.1004006 http://www.jimmunol.org/content/187/6/2841 Downloaded from

References This article cites 103 articles, 44 of which you can access for free at: http://www.jimmunol.org/content/187/6/2841.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online.

• Rapid Reviews! 30 days* from submission to initial decision

• No Triage! Every submission reviewed by practicing scientists

• Fast Publication! 4 weeks from acceptance to publication

by guest on October 2, 2021 *average

Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts

The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The BTB-ZF Family of Transcription Factors: Key Regulators of Lineage Commitment and Effector Function Development in the Immune System Aimee M. Beaulieu* and Derek B. Sant’Angelo*,†,‡ Successful immunity depends upon the activity of mul- 1, -2, -4, -5, and -7 (1–11). Although most of these interac- tiple cell types. Commitment of pluripotent precursor tions were described in nonhematopoietic cells or transformed cells to specific lineages, such as T or B cells, is obviously cell lines, BTB-ZF likely regulate expression in fundamental to this process. However, it is also becom- primary lymphocytes via a similar mechanism. For example, ing clear that continued differentiation and specializa- the BTB-ZF PLZP has been shown to associate with + + tion of lymphoid cells is equally important for immune HDAC-2 in Th2-skewed CD4 and CD8 T cells, and these system integrity. Several members of the BTB-ZF family two proteins colocalize at regulatory elements in the IL-13 gene Downloaded from have emerged as critical factors that control development where they likely act in concert to modulate transcription (12). of specific lineages and also of specific effector subsets In addition to corepressor recruitment, the BTB domain, within these lineages. For example, BTB-ZF have and in some cases the ZF domain, also facilitate hetero- been shown to control T cell versus B cell commitment dimerization and homodimerization among the different gene family members. For example, the BTB-ZF protein Bcl-6 can andCD4versusCD8lineagecommitment.Others, exist as a homodimer (13) but may also form heterodimers http://www.jimmunol.org/ such as PLZF for NKT cells and Bcl-6 for T follicular with other BTB-ZF proteins, including NAC-1, PLZF, LRF, helper cells, are necessary for the acquisition of effec- BAZF, and Miz-1 (14–18). Similarly, overexpression and tor functions. In this review, we summarize current find- cotransfection systems have demonstrated an interaction be- ings concerning the BTB-ZF family members with a tween PLZF and PLZP, although PLZF can also exist as reported role in the immune system. The Journal of a homodimer (1, 19, 20). Like the cofactor studies, nearly Immunology, 2011, 187: 2841–2847. all of this work has been done in nonhematopoietic cells or cell lines; nevertheless, the finding that Miz-1 and Bcl-6

physically interact in primary germinal center B cells (18) by guest on October 2, 2021 road complex, tramtrack, bric-a-brac, and zinc finger suggests that heterodimerization may be physiologically rele- (BTB-ZF) proteins are an evolutionarily conserved vant to BTB-ZF protein function in primary cells of the B family of transcriptional regulators. Members of this immune system, and further studies are needed to shed light group, of which there are .45 in human and mice, are char- on this topic. acterized as having one or more C-terminal C2H2 Kru¨ppel- type zinc finger DNA binding domains in combination with BTB-ZF proteins control lineage commitment, development, and an N-terminal BTB domain that mediates protein–protein function in lymphocytes interactions. Transcriptional regulation, most often repres- As powerful regulators of , BTB-ZF proteins sion, is achieved by sequence-specific binding by the ZF do- are critical players in a wide variety of biological processes, main to regulatory regions in target genes, coupled with the re- including developmental events such as gastrulation and limb cruitment of cofactors involved in chromatin remodeling and formation, control of DNA damage and cell cycle progression transcriptional silencing/activation. in normal and oncogenic tissues, maintenance of the stem cell Cofactor complex formation is largely mediated by the BTB pool, and gamete formation (21). Moreover, recent studies domain, which has been shown to interact directly with core- have highlighted a fundamental and nonredundant role for pressors and histone modification enzymes, including SMRT, many BTB-ZF factors in the development and function of ETO,N-Cor,B-Cor, CtBP,Sin3A, DRAL/FHL2,andHDAC- cells in the immune system. This review will summarize

*Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Abbreviations used in this article: BAZF, Bcl-6–associated zinc finger; BTB-ZF, broad Center, New York, NY 10065; †Louis V. Gerstner Jr. Graduate School of Biomedical complex, tramtrack, bric-a-brac, and zinc finger; CSR, class switch recombination; GC, Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; and ‡Weill germinal center; iNKT, invariant NKT; LRF, leukemia/lymphoma related factor; Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, MAZR, -associated zinc-finger protein-related factor; Miz-1, Myc-interacting zinc 10065 finger protein-1; PLZF, promyelocytic leukemia zinc finger; PLZP, PLZF-like zinc finger protein; SHM, somatic hypermutation; Tfh, T follicular helper; ThPOK, Th- Received for publication May 13, 2011. Accepted for publication June 22, 2011. inducing POZ/Kru¨ppel-like factor. This work was supported by the National Institute of Allergy and Infectious Diseases (Grants R01 AI083988 and R01 AI059739). A.M.B. was supported by a National Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 Institutes of Health National Service Research award (Grant T32 CA009149). Address correspondence and reprint requests to Dr. Derek B. Sant’Angelo, Immunology Program, Memorial Sloan-Kettering Cancer Center, Box 492, 1275 York Avenue, New York, NY 10021. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.1004006 2842 BRIEF REVIEWS: BTB-ZF GENES IN THE IMMUNE SYSTEM current findings on the eight family members with known cellular senescence in response to RAG-induced DNA lesions. roles in orchestrating lymphocyte development: Bcl-6, PLZF, Consequently, Bcl-6–deficient mice have an immature B cell Th inducing POZ/Kru¨ppel-like factor (ThPOK), PLZP, pool that is reduced in both size and clonal diversity (34). MAZR, BAZF, LRF, and Miz-1 (Fig. 1). Hints at a role for Bcl-6 in T cell function originated from Bcl-6. The BTB-ZF protein Bcl-6 was first identified as an early studies in which Bcl-6–deficient mice were found to oncogene in diffuse large B cell lymphoma, the most com- develop spontaneous Th2 inflammation, characterized by mon form of non-Hodgkin’s lymphoma. The transformative enhanced IgE production and severe eosinophilia (27, 28). properties of Bcl-6 stem largely from its ability to repress Upon stimulation in vitro, T cells from Bcl-6–deficient mice transcription of tumor suppressor and cell cycle arrest genes, produce elevated levels of IL-4, IL-5, and IL-13, a phenotype including , ATR, CHEK1, and CDKN1A/p21 (18, that has been linked to direct binding by Bcl-6 in regulatory 22–26). Bcl-6 is normally expressed at high levels in ger- regions of genes for IL-5, Ig«, and IL-4 (27, 35, 36). minal center (GC) B cells. Early studies showed that mice More recently, Bcl-6 was shown to be necessary and suf- lacking Bcl-6 were unable to form GCs after immunization ficient for the development of CD4+ T follicular helper (Tfh) with T cell-dependent Ags. Moreover, Ag-specific B cells in cells, which provide critical help to GC B cells undergoing these mice were impaired for affinity maturation and class SHM and CSR (37–39). Constitutive Bcl-6 expression in switch recombination (CSR) to IgG subtypes (27, 28). Re- CD4+ T cells in vivo drives nearly complete commitment to constitution of RAG1-knockout mice with Bcl-6–deficient the Tfh lineage, and these helper cells are highly effective bone marrow showed that Bcl-6 was required in the hema- inducers of GC formation and Ab production by B cells. topoietic compartment for GC formation and somatic Conversely, Bcl-6 deficiency abrogates Tfh cell differentia- Downloaded from hypermutation (SHM) but not for primary IgG responses tion, and CD4+ T cells from these mice fail to mediate GC (29, 30). Bcl-6 also represses expression of Blimp-1, a formation (38, 39). At a mechanistic level, Bcl-6 is induced in that promotes plasma cell differentiation CD4+ T cells by IL-6 and IL-21, although neither cytokine is (31, 32). Given that Blimp-1 represses Bcl-6, the reciprocal independently required for Tfh cell differentiation (40). Bcl-6 antagonism of these two genes has been proposed to serve as drives expression of molecules involved in Tfh cell homing http://www.jimmunol.org/ a bimodal “switch,” by which B cell fate, as either a GC B cell and function, including CXCR5, CXCR4, IL-21R, IL-6R, or an Ab-secreting plasma cell, is established and maintained PD-1, and IL-21, and is required to maintain Tfh identity (33). Beyond promoting GC formation and suppressing by suppressing the expression of factors associated with other plasma cell gene programs, Bcl-6 inhibits cell cycle arrest Th cell lineages, including IFN-g, IL-17, T-bet, IL-4, GATA- and apoptosis in GC B cells, allowing DNA damage, a nat- 3, and Blimp-1 (37–39). As in B cells, Blimp-1 and Bcl-6 ural byproduct of CSR and SHM, to occur in the absence counter-repress each other and play antagonistic roles in of cell cycle checkpoint activation. To this end, it represses CD4+ T cell differentiation, with Blimp-1 suppressing and many of the same genes dysregulated during Bcl-6–mediated Bcl-6 promoting Tfh lineage commitment (39). transformation, including p53, ATR, CHEK1, and CDKN1A/ Bcl-6 is also expressed at high levels in memory CD8+ T cells. by guest on October 2, 2021 p21 (18, 24–26). In mice lacking Bcl-6, CD8+ T cells proliferate poorly and fail In addition to peripheral lineage commitment, Bcl-6 is to develop into central memory cells, highlighting a critical role important for B cell development in the bone marrow (34). for Bcl-6 in memory T cell formation. Overexpression of Bcl-6 High Bcl-6 expression is induced by pre-BCR signaling leads to increased numbers of central memory CD8+ T cells during the pro- to pre-B cell transition. Bcl-6 in turn sup- after immunization and enhances CD8+ T cell proliferation presses DNA damage response genes, including CDKN1A/ after secondary stimulation (41). Similarly, Bcl-6–deficient p21, CDKN1B/p27, and CDKN2A/Arf, during Ig L chain CD4+ T cells exhibit increased apoptosis at the effector cell rearrangement, which would otherwise activate apoptosis and stage and fail to persist as long-lived memory cells (42). Beyond

FIGURE 1. The key structural features of the eight BTB-ZF transcription factors discussed in this review are highlighted, and the reported functions of each tran- scription factor are listed. The Journal of Immunology 2843 its role in traditional T cell subsets, Bcl-6 is also important for PLZF may also impact NK cell function either directly the function of human CD8+ T suppressor cells, which may or indirectly; PLZF deficiency impairs protection against play a role in immunological tolerance in transplantation set- Semliki Forest virus infection, and this susceptibility was as- tings (43). sociated with reduced IFN-induced NK cell cytotoxicity (63). PLZF. Like Bcl-6, the BTB-ZF protein promyelocytic leukemia Given the innate lymphocyte features of all of these cells, zinc finger (PLZF) was first identified in the context of hema- future studies will be useful for understanding the role of topoietic cancer. In acute promyelocytic leukemia, chromo- PLZF in their development and/or function. somal translocation fuses the genes for PLZF and the nu- ThPOK. ThPOK, also known as Zbtb7b or cKrox, encodes a clear retinoic acid a, ultimately leading to oncogenic three-zinc-finger BTB domain protein originally identified as transformation (44). In keeping with a putative function as a regulator of development and function in cells from connec- a tumor suppressor gene in acute promyelocytic leukemia, tive tissues. Within the hematopoietic compartment, ThPOK PLZF has been associated with cellular quiescence and growth is upregulated in CD4+,butnotCD8+, T cells upon dif- suppression in nontransformed cells of hematopoietic and ferentiation from double- to single-positive thymocytes, and nonhematopoietic origin (45–51). its expression is stably maintained in CD4+ T cells (64, 65). Recent studies on PLZF have elucidated its function as a A spontaneous mutation in one of its zinc finger domains critical regulator of innate T cell lineages. PLZF is highly ex- resulted in the loss of Th cells in helper deficient mice (65). pressed in immature CD1d-restricted invariant NKT (iNKT) MHC class II-restricted T cells from HD mice, as well as T cells cells. In PLZF-deficient mice, iNKT cells fail to undergo with submaximal ThPOK expression, exhibit features of thymic expansion and are substantially reduced in the thymus, transdifferentiation to the CD8+ T cell lineage, highlighting Downloaded from liver, and spleen. The iNKT cells that do develop in these mice a critical role for ThPOK in driving the CD4+ versus CD8+ behave more like conventional naive T cells: these cells pref- lineage fate in naive T cells (65, 66). Indeed, constitutive erentially traffic to the lymph nodes and fail to express ThPOK expression in developing thymocytes induces redirec- characteristic activation markers (e.g., CD44 and CD69). tion to the CD4+ lineage, even among MHC class I-restricted Moreover, PLZF-deficient iNKT cells show a marked re- cells, with many of the features of Th cells (65). http://www.jimmunol.org/ duction in cytokine secretion upon primary stimulation— In a temporal and developmental sense, ThPOK functions most notable is their inability to produce simultaneously both downstream of GATA-3, an early CD4+ lineage transcription IL-4 and IFN-g—and instead require secondary activation to factor, and ThPOK upregulation in conventional thymocytes elaborate effector responses fully (52, 53). In contrast, ectopic appears to depend on effective TCR signaling at the CD4+ 2 PLZF expression in T cells results in the spontaneous acqui- CD8lo stage (67–69). MHC class II-signaled CD4+CD8 sition of memory/effector phenotypes and functions. PLZF- thymocytes with impaired signaling through the TCR- transgenic T cells exhibit an activated phenotype (e.g., associated kinases, Zap70 or Itk, fail to upregulate ThPOK CD44hi and CD62Llo), migrate to nonlymphoid tissues, and and instead express cytotoxic T cell markers, including the show enhanced cytokine production upon primary activation transcription factor Runx3 and its targets, and by guest on October 2, 2021 even in the absence of costimulation (52, 54, 55). perforin (70–72). Analogous to the antagonistic relationship In addition to iNKT cells, PLZF expression was recently of Blimp-1 and Bcl-6 in B-cell differentiation, ThPOK and shown in a subset of mature gd T cells expressing the the CD8+ T cell determinant, Runx3, counter-repress ex- Vg1.1Vd6.3 TCR (56, 57). Vg1.1Vd6.3 T cells share many pression of each other. Thus, Runx-deficient MHC class I- features with abTCR-expressing iNKT cells, including consti- restricted thymocytes, which lack functionality in both Runx3 tutive expression of activation markers, rapid and simultaneous and Runx1 or are genetically deficient for the obligatory Runx production of IFN-g and IL-4, requiring the SLAM-associated binding protein, Cbfb, retain ThPOK expression and exhibit adapter protein for their development. Although PLZF- features of the Th cell lineage, showing that Runx-mediated deficient mice harbored normal numbers of Vg1.1+Vd6.3+ silencing of ThPOK is required to maintain CD8+ lineage T cells, their function is dramatically impaired in the ab- commitment (73). Surprisingly, in animals lacking both sence of PLZF. Indeed, in contrast to wild-type cells, PLZF- Cbfb and ThPOK, MHC class II-restricted thymocytes main- deficient Vg1.1+Vd6.3+ T cells produce almost undetectable tain Th cell characteristics, suggesting that in settings where levels of IFN-g and IL-4 in response to TCR stimulation (57, commitment to the CD8+ T cell lineage is intrinsically lim- 58). Notably, transgenic mice expressing the Vg1.1+Vd6.4+ ited (i.e., as a result of Runx deficiency), ThPOK is more TCR have large numbers of PLZF-positive T cells and develop important for the maintenance, rather than the induction, of spontaneous dermatitis, perhaps underscoring a proinflamma- the CD4+ T cell fate (74). Nevertheless, in mice capable of tory and sometimes pathogenic role for these cells (56). CD8+ versus CD4+ fate decisions, ThPOK plays a critical and Several mouse strains have been described with increased active role in repressing CD8+ T cell lineage commitment. numbers of innate CD8+ T cells, including mice lacking Recent studies have uncovered critical roles for ThPOK the Tec kinase Itk (59), the coactivator CBP (60), and the in the development and function of other T cells subsets. In transcription factor KLF2 (61). Recently, this CD8+ T cell mature CD8+ T cells, ThPOK expression is upregulated as a expansion was shown to be a cell-extrinsic consequence of result of TCR activation and is required for effective expansion elevated IL-4 produced by an expanded PLZF-positive T cell during the primary and secondary responses to acute viral population in these mice (61). infection (75). In mice lacking functional ThPOK, memory In addition to ab and gd NKT cell subsets, PLZF is ex- CD8+ T cells are impaired for IL-2 secretion and granzyme pressed in human MR1-specific mucosal-associated invariant B expression after Ag rechallenge (75). In innate T cell line- T cells and in fetal MHC class II-restricted T cells that de- ages, ThPOK controls the development and functional matu- velop as a result of positive selection on other T cells (52, 62). ration of PLZF-positive NKT cells of both the gd and ab TCR 2844 BRIEF REVIEWS: BTB-ZF GENES IN THE IMMUNE SYSTEM lineages (57, 76–78). ThPOK is highly expressed in Vg1.1+ fected airways (83). Similarly, these mice exhibit heightened Vd6.3+ gd T cells and CD4+ iNKT cells. Although ThPOK Th2 inflammation in the context of a hapten-induced model deficiency does not significantly alter the frequency of either of contact hypersensitivity, leading to exacerbated edema and population in mice, both subsets show dramatically impaired mast cell degranulation at reaction sites and increased levels of CD4 coreceptor expression, much like conventional T cells (57, IgE and hapten-specific IgG Abs in the circulation (84). These 76, 78). In addition, a separate study reported a reduction in the defects are directly linked to a cell-intrinsic requirement for total pool of mature CD24-negative gd T cells, particularly PLZP in T cells, as transfer of PLZP-deficient or PLZP- those expressing NK1.1, in ThPOK-deficient mice, suggestive overexpressing T cells exacerbated or ameliorated, respecti- of a broader role for ThPOK in the development of some, al- vely, disease progression in wild-type animals. Thus, addi- though not all, gd T cell subsets (77). More striking, however, is tional studies will be needed to clarify the exact role of PLZP + the role of ThPOK in the effector function of iNKT and Vg1.1 in lymphocyte function in vivo. + Vd6.3 gd T cells. ThPOK-deficient iNKT cells show impaired Beyond regulating cytokine production in T cells, PLZP expression of markers associated with NKT function, including may also play a role in lineage commitment during T cell granzyme B, CD69, and, in one study, NK1.1, and produce less development. In one study, overexpression of PLZP in de- IL-4, IFN-g,andTNF-a in response to aGal-Cer stimula- veloping double-positive thymocytes, in the context of a fetal tion (76, 78). As in conventional T cells, ThPOK expression thymic organ culture model, led to a preferential accumula- + in iNKT cells depends on GATA-3 (76). Similarly, Vg1.1 tion of single-positive CD8+ T cells. Similar to its function + Vd6.3 gd T cells produce less IL-4, but more IFN-g, in re- in mature T cells, this accumulation was linked to the ability Downloaded from sponse to stimulation, and this impairment correlated with of PLZP to inhibit GATA-3 function (85). reduced PLZF expression (57). BAZF. The Bcl-6–associated zinc finger (BAZF) protein, also PLZP. The BTB protein PLZF-like zinc finger protein (PLZP), known as Bcl-6b, is a five-zinc-finger BTB protein with high also known as FAZF, TZFP, and ROG, shares many features similarity to Bcl-6. In addition to sharing significant sequence with PLZF, including a high level of sequence similarity, homology, both can recognize the same target DNA sequences recognition of the same target DNA sequences, and declin- (17). Within in the lymphocyte compartment, BAZF mRNA is http://www.jimmunol.org/ ing expression in hematopoietic progenitors cells as a func- detectable in CD4+ and CD8+ naive T cells (86). Notably, tion of lineage-specific differentiation (19, 79, 80). Among both Bcl-6– and BAZF-deficient animals exhibit aberrant he- lymphocytes, PLZP is upregulated in primary CD4+ and + matopoietic progenitor cell proliferation, a defect that was CD8 T cells after TCR activation in vitro (12, 80, 81). linked to a cell-intrinsic requirement for BAZF in CD8+ T cells from PLZP-deficient mice produce more IL-2 and T cells (87). In addition to naive T cells, BAZF is expressed at are hyperproliferative in response to TCR stimulation com- high levels in some Ag-specific, memory CD8+ T cells, and, pared with wild-type cells, suggesting an antiproliferative role although BAZF-deficient mice show normal CD8+ T cell for PLZP in activated T cells (80, 82).

activation in response to primary viral infection, recall by guest on October 2, 2021 In addition to controlling proliferation, several studies responses by memory CD8+ T cells are greatly impaired have highlighted a role for PLZP in controlling lymphocyte in vitro and in vivo (88). cytokine responses. When overexpressed in T cell lines, PLZP + In contrast to the role of BAZF in memory CD8 T cells, was shown to interact directly with the Th2-promoting tran- naive CD4+ T cells require BAZF expression for maxi- scription factor GATA-3 and could antagonize GATA-3 mal TCR-induced proliferation in vitro, whereas memory binding to target genes, such as IL-5 (81). Similarly, PLZP CD4+ T cells do not (86). Moreover, naive CD4+ T cells repressed GATA-3–induced IL-4 production when both from mice that ectopically express BAZF are hyperprolifer- transcription factors were cotransfected into primary CD4+ ative in response to TCR stimulation, but memory CD4+ T cells (12). Moreover, overexpression in either Th1- or Th2- T cells from these mice behave normally. skewed T cells impaired cytokine production on a more global level, leading to reduced IL-4, IL-5, IL-10, IFN-g, and MAZR. Compared with the BTB-ZF proteins detailed ear- IL-17 (12, 81). In Tc2-skewed CD8+ T cells, endogenous lier, relatively little is known about the role of the Myc- PLZP was shown to bind directly a regulatory region in the associated zinc-finger protein-related factor (MAZR) in IL-13 gene, hinting at a similar role for PLZP in cytokine lymphocyte and development. MAZR is expressed in thy- production by CD8+ T cells (12). mocytes and B cells and, in the latter, activated c-Myc in Consistent with the overexpression studies, CD4+ T cells overexpression studies (89). In double-negative thymocytes, from PLZP-deficient mice express higher levels of IL-4, IL-5, MAZR has been postulated to function as a transcriptional and IL-13 when stimulated in vitro under Th2-promoting repressor of the Cd8 locus, and its downregulation is re- culture conditions, and PLZP-deficient CD8+ T cells pro- quired, in part, for CD8 expression at the transition to the duced more IFN-g upon stimulation under neutral con- double-positive stage (90). In double-positive thymocytes, ditions (80). Nevertheless, PLZP-deficient CD4+ T cells are ectopically expressed MAZR could bind enhancer elements fully capable of differentiating into Th1 or Th2 cells in vitro, in the Cd8 gene and suppress CD8 expression (90). Recent and PLZP-deficient mice mount normal Th1 and Th2 re- studies, however, show that MAZR deficiency is insuffi- sponses to myelin oligodendrocyte glycoprotein-induced cient to allow CD8 expression in double-negative thymocytes. experimental autoimmune encephalomyelitis and keyhole Instead, development of single-positive CD8+ T cells was limpet hemocyanin immunization, respectively (82). In impaired in these animals, and MHC class I-restricted thymo- contrast, allergic responses in airway hypersensitivity models cytes were redirected into the CD4+ lineage, leading to an are enhanced in PLZP-deficient mice, reflecting increased increased CD4+ to CD8+ T cell ratio among mature thy- Th2 differentiation and Th2-driven inflammation in the af- mocytes and peripheral T cells. This phenotype was linked The Journal of Immunology 2845 to MAZR-mediated repression of the ThPOK gene in double- investigation of the cofactors recruited by these proteins for positive thymocytes (91). the purpose of regulating target gene transcription, as well as LRF. Leukemia/lymphoma related factor (LRF), also known the identity of the gene targets themselves. In addition, - as OCZF, Zbtb7a, FBI-1, and Pokemon, is a BTB-ZF trans- tively little is known about the upstream signals that regulate criptional repressor and oncogene associated with malignancy the spatial/temporal function of these transcription factors in lymphomas and solid epithelial tumors, including breast in distinct lymphocyte lineages. In this vein, several studies cancer, and non-small cell lung carcinoma (92–94). LRF is have highlighted posttranslational modification of BTB-ZF expressed in a broad range of myeloid and lymphoid lineages, proteins as an important regulatory signal controlling their including most subsets of developing and peripheral B cells expression and function. For example, acetylation and su- (95). Conditional deletion of the LRF gene in hematopoietic moylation of PLZF may promote DNA binding and tran- stem cells in vivo led to a profound reduction in peripheral scriptional repression (98–100), and acetylation of ThPOK B cells, consistent with a cell-intrinsic requirement for LRF blocks ubiquitin-mediated degradation, thereby stabilizing its + for progression past the prepro-B cell stage during bone mar- expression in CD4 T cells (101). In contrast, phosphoryla- row development (93, 95). Unexpectedly, these mice exhib- tion of PLZF and Bcl-6, by CDK2 and ATM, respectively, ited extrathymic T cell development in the bone marrow. has been shown to trigger ubiquitylation and degradation via Additional experiments revealed that LRF was required in proteasome-dependent pathways (102, 103). lymphoid progenitor cells in the bone marrow to suppress From development to effector function, recent studies Notch-dependent T cell lineage commitment and allow B cell have highlighted a central and indispensable role for BTB- development to progress. In the absence of LRF, Notch genes ZF transcription factors in controlling nearly every aspect Downloaded from were aberrantly upregulated in hematopoietic progenitors, ab- of lymphocyte biology. Moreover, the fact that fewer than rogating B cell development and driving spontaneous T cell 10 of the .45 factors in this protein family have been eval- development outside of the thymus (95). It remains to be uated in this context suggests that future work is likely to determined whether Notch is a direct target of LRF or uncover additional BTB-ZF proteins with roles in lymphocyte whether aberrant Notch signaling in these mice is an indirect function, fate, and phenotype. http://www.jimmunol.org/ consequence of impaired LRF-dependent signals. Miz-1. A critical role for Myc-interacting zinc finger protein-1 Acknowledgments (Miz-1) in lymphocyte development has recently been appre- We are grateful for the engaging and challenging intellectual environment ciated. In the past year, two separate studies using Miz-1– created by the staffs of the Sant’Angelo, Denzin, and Chaudhuri laboratories. defective mice revealed an essential function for Miz-1 in the development of both T and B lymphocytes (96, 97). Animals Disclosures lacking the BTB domain of Miz-1 exhibit a profound reduc- The authors have no financial conflicts of interest. tion in the number of thymic early T cell progenitor cells. Moreover, T cell development in these animals is blocked at by guest on October 2, 2021 the double-negative to double-positive transition causing a References 1. Melnick, A., G. Carlile, K. F. Ahmad, C. L. Kiang, C. Corcoran, V. Bardwell, severe reduction in thymic cellularity, which was mirrored G. G. Prive, and J. D. Licht. 2002. Critical residues within the BTB domain by specific reductions in the number of ab and gd T cells. of PLZF and Bcl-6 modulate interaction with corepressors. Mol. Cell. Biol. 22: 1804–1818. Transfer of Miz-1–deficient hematopoietic progenitors into 2. Chauchereau, A., M. Mathieu, J. de Saintignon, R. Ferreira, L. L. Pritchard, wild-type mice confirmed that the requirement for Miz-1 in Z. Mishal, A. Dejean, and A. Harel-Bellan. 2004. HDAC4 mediates transcrip- T cell development was cell intrinsic. Consistently, pro-T cells tional repression by the acute promyelocytic leukaemia-associated protein PLZF. Oncogene 23: 8777–8784. from these mice failed to differentiate in vitro as a result of 3. Lemercier, C., M. P. Brocard, F. Puvion-Dutilleul, H. Y. Kao, O. Albagli, and increased apoptosis (96). In addition to the T cell defect, S. Khochbin. 2002. Class II histone deacetylases are directly recruited by BCL6 transcriptional repressor. J. Biol. Chem. 277: 22045–22052. Miz-1 deficiency leads to a complete loss of follicular B cells, 4. Tao, R. H., H. Kawate, Y. Wu, K. Ohnaka, M. Ishizuka, A. Inoue, H. Hagiwara, underscoring a parallel role for Miz-1 in the development of and R. Takayanagi. 2006. Testicular zinc finger protein recruits histone deacetylase 2 and suppresses the transactivation function and intranuclear foci formation of certain B cell subsets (97). In both lymphocyte populations, agonist-bound competitively with TIF2. Mol. Cell. Endocrinol. Miz-1 was shown to be required downstream of IL-7R sig- 247: 150–165. 5. Brenner, C., R. Deplus, C. Didelot, A. Loriot, E. Vire´, C. De Smet, A. Gutierrez, naling in lymphocyte progenitor populations to promote D. Danovi, D. Bernard, T. Boon, et al. 2005. Myc represses transcription through STAT5 activation and expression of the antiapoptotic protein recruitment of DNA methyltransferase corepressor. EMBO J. 24: 336–346. Bcl-2 (96, 97). In developing T cells, these effects were 6. Barna, M., T. Merghoub, J. A. Costoya, D. Ruggero, M. Branford, A. Bergia, B. Samori, and P. P. Pandolfi. 2002. Plzf mediates transcriptional repression mediated in part by Miz-1–dependent repression of the of HoxD gene expression through chromatin remodeling. Dev. Cell 3: 499–510. STAT inhibitor SOCS-1; consistent with this, binding of 7. Jeon, B. N., J. Y. Yoo, W. I. Choi, C. E. Lee, H. G. Yoon, and M. W. Hur. 2008. Proto-oncogene FBI-1 (Pokemon/ZBTB7A) represses transcription of the tumor Miz-1 to the SOCS-1 promoter could be detected in pri- suppressor Rb gene via binding competition with Sp1 and recruitment of co- mary double-negative thymocytes. A similar relationship be- repressors. J. Biol. Chem. 283: 33199–33210. 8. McLoughlin, P., E. Ehler, G. Carlile, J. D. Licht, and B. W. Scha¨fer. 2002. The tween SOCS-1 and Miz-1 was observed in developing B cells, LIM-only protein DRAL/FHL2 interacts with and is a corepressor for the pro- although loss of Miz-1 also abrogated expression of two tran- myelocytic leukemia zinc finger protein. J. Biol. Chem. 277: 37045–37053. scription factors, Tcf3 and Ebf1, critical for the survival and 9. Laudes, M., R. Bilkovski, F. Oberhauser, A. Droste, M. Gomolka, U. Leeser, M. Udelhoven, and W. Krone. 2008. Transcription factor FBI-1 acts as a dual function of early B cell progenitors (97). regulator in adipogenesis by coordinated regulation of cyclin-A and -4. J. Mol. Med. 86: 597–608. 10. Costoya, J. A. 2007. Functional analysis of the role of POK transcriptional Conclusions repressors. Brief. Funct. Genomics Proteomics 6: 8–18. New studies are required to delineate further the exact mo- 11. Ci, W., J. M. Polo, and A. Melnick. 2008. B-cell lymphoma 6 and the molecular pathogenesis of diffuse large B-cell lymphoma. Curr. Opin. Hematol. 15: 381–390. lecular mechanisms by which BTB-ZF proteins regulate gene 12. Omori, M., M. Yamashita, M. Inami, M. Ukai-Tadenuma, M. Kimura, Y. Nigo, expression in lymphocytes. This will require a more thorough H. Hosokawa, A. Hasegawa, M. Taniguchi, and T. Nakayama. 2003. CD8 T cell- 2846 BRIEF REVIEWS: BTB-ZF GENES IN THE IMMUNE SYSTEM

specific downregulation of histone hyperacetylation and gene activation of the IL-4 38. Nurieva, R. I., Y. Chung, G. J. Martinez, X. O. Yang, S. Tanaka, T. D. Matskevitch, gene locus by ROG, repressor of GATA. Immunity 19: 281–294. Y. H. Wang, and C. Dong. 2009. Bcl6 mediates the development of T follicular 13. Dhordain, P., O. Albagli, S. Ansieau, M. H. Koken, C. Deweindt, S. Quief, helper cells. Science 325: 1001–1005. D. Lantoine, A. Leutz, J. P. Kerckaert, and D. Leprince. 1995. The BTB/POZ 39. Johnston, R. J., A. C. Poholek, D. DiToro, I. Yusuf, D. Eto, B. Barnett, domain targets the LAZ3/BCL6 oncoprotein to nuclear dots and mediates A. L. Dent, J. Craft, and S. Crotty. 2009. Bcl6 and Blimp-1 are reciprocal homomerisation in vivo. Oncogene 11: 2689–2697. and antagonistic regulators of T follicular helper cell differentiation. Science 325: 14. Davies, J. M., N. Hawe, J. Kabarowski, Q. H. Huang, J. Zhu, N. J. Brand, 1006–1010. D. Leprince, P. Dhordain, M. Cook, G. Morriss-Kay, and A. Zelent. 1999. Novel 40. Poholek, A. C., K. Hansen, S. G. Hernandez, D. Eto, A. Chandele, BTB/POZ domain zinc-finger protein, LRF, is a potential target of the LAZ-3/ J. S. Weinstein, X. Dong, J. M. Odegard, S. M. Kaech, A. L. Dent, et al. 2010. BCL-6 oncogene. Oncogene 18: 365–375. In vivo regulation of Bcl6 and T follicular helper cell development. J. Immunol. 15. Korutla, L., P. Wang, T. G. Jackson, and S. A. Mackler. 2009. NAC1, a POZ/ 185: 313–326. BTB protein that functions as a corepressor. Neurochem. Int. 54: 245–252. 41. Ichii, H., A. Sakamoto, Y. Kuroda, and T. Tokuhisa. 2004. Bcl6 acts as an 16. Dhordain, P., O. Albagli, N. Honore, F. Guidez, D. Lantoine, M. Schmid, amplifier for the generation and proliferative capacity of central memory CD8+ H. D. The, A. Zelent, and M. H. Koken. 2000. Colocalization and hetero- T cells. J. Immunol. 173: 883–891. merization between the two human oncogene POZ/zinc finger proteins, LAZ3 42. Ichii, H., A. Sakamoto, M. Arima, M. Hatano, Y. Kuroda, and T. Tokuhisa. 2007. (BCL6) and PLZF. Oncogene 19: 6240–6250. Bcl6 is essential for the generation of long-term memory CD4+ T cells. 17. Okabe, S., T. Fukuda, K. Ishibashi, S. Kojima, S. Okada, M. Hatano, M. Ebara, Int. Immunol. 19: 427–433. H. Saisho, and T. Tokuhisa. 1998. BAZF, a novel Bcl6 homolog, functions as 43. Chang, C. C., G. Vlad, V. D. D’Agati, Z. Liu, Q. Y. Zhang, P. Witkowski, a transcriptional repressor. Mol. Cell. Biol. 18: 4235–4244. A. A. Torkamani, M. B. Stokes, E. K. Ho, R. Cortesini, and N. Suciu-Foca. 2010. 18. Phan, R. T., M. Saito, K. Basso, H. Niu, and R. Dalla-Favera. 2005. BCL6 BCL6 is required for differentiation of Ig-like transcript 3-Fc-induced CD8+ interacts with the transcription factor Miz-1 to suppress the cyclin-dependent kinase T suppressor cells. J. Immunol. 185: 5714–5722. inhibitor p21 and cell cycle arrest in germinal center B cells. Nat. Immunol. 44. Zelent, A., F. Guidez, A. Melnick, S. Waxman, and J. D. Licht. 2001. Trans- 6: 1054–1060. locations of the RARalpha gene in acute promyelocytic leukemia. Oncogene 20: 19. Hoatlin, M. E., Y. Zhi, H. Ball, K. Silvey, A. Melnick, S. Stone, S. Arai, N. Hawe, 7186–7203. G. Owen, A. Zelent, and J. D. Licht. 1999. A novel BTB/POZ transcriptional 45. Good, K. L., and S. G. Tangye. 2007. Decreased expression of Kruppel-like factors

repressor protein interacts with the Fanconi anemia group C protein and PLZF. in memory B cells induces the rapid response typical of secondary antibody Downloaded from Blood 94: 3737–3747. responses. Proc. Natl. Acad. Sci. USA 104: 13420–13425. 20. Melnick, A., K. F. Ahmad, S. Arai, A. Polinger, H. Ball, K. L. Borden, 46. Joko, T., D. Nanba, F. Shiba, K. Miyata, A. Shiraishi, Y. Ohashi, and G. W. Carlile, G. G. Prive, and J. D. Licht. 2000. In-depth mutational analysis S. Higashiyama. 2007. Effects of promyelocytic leukemia zinc finger protein on of the promyelocytic leukemia zinc finger BTB/POZ domain reveals motifs the proliferation of cultured human corneal endothelial cells. Mol. Vis. 13: and residues required for biological and transcriptional functions. Mol. Cell. Biol. 649–658. 20: 6550–6567. 47. Shiraishi, A., T. Joko, S. Higashiyama, and Y. Ohashi. 2007. Role of promyelo- 21. Kelly, K. F., and J. M. Daniel. 2006. POZ for effect—POZ-ZF transcription cytic leukemia zinc finger protein in proliferation of cultured human corneal factors in cancer and development. Trends Cell Biol. 16: 578–587. endothelial cells. Cornea 26 (9, Suppl 1): S55–S58. http://www.jimmunol.org/ 22. Kawamata, N., T. Miki, T. Fukuda, S. Hirosawa, and N. Aoki. 1994. The 48. Kikugawa, T., Y. Kinugasa, K. Shiraishi, D. Nanba, K. Nakashiro, N. Tanji, organization of the BCL6 gene. Leukemia 8: 1327–1330. M. Yokoyama, and S. Higashiyama. 2006. PLZF regulates Pbx1 transcription 23. Cattoretti, G., L. Pasqualucci, G. Ballon, W. Tam, S. V. Nandula, Q. Shen, and Pbx1-HoxC8 complex leads to androgen-independent prostate cancer pro- T. Mo, V. V. Murty, and R. Dalla-Favera. 2005. Deregulated BCL6 expression liferation. Prostate 66: 1092–1099. 49. Felicetti, F., M. C. Errico, L. Bottero, P. Segnalini, A. Stoppacciaro, M. Biffoni, recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. N. Felli, G. Mattia, M. Petrini, M. P. Colombo, et al. 2008. The promyelocytic Cancer Cell 7: 445–455. leukemia zinc finger-microRNA-221/-222 pathway controls melanoma pro- 24. Ranuncolo, S. M., J. M. Polo, and A. Melnick. 2008. BCL6 represses CHEK1 and gression through multiple oncogenic mechanisms. Cancer Res. 68: 2745–2754. suppresses DNA damage pathways in normal and malignant B-cells. Blood Cells 50. Shiraishi, K., K. Yamasaki, D. Nanba, H. Inoue, Y. Hanakawa, Y. Shirakata, Mol. Dis. 41: 95–99. K. Hashimoto, and S. Higashiyama. 2007. Pre-B-cell leukemia transcription factor 25. Ranuncolo, S. M., L. Wang, J. M. Polo, T. Dell’Oso, J. Dierov, T. J. Gaymes, 1 is a major target of promyelocytic leukemia zinc-finger-mediated melanoma cell F. Rassool, M. Carroll, and A. Melnick. 2008. BCL6-mediated attenuation growth suppression. Oncogene 26: 339–348. of DNA damage sensing triggers growth arrest and senescence through a p53- by guest on October 2, 2021 51. Bernardo, M. V., E. Yelo, L. Gimeno, J. A. Campillo, and A. Parrado. 2007. dependent pathway in a cell context-dependent manner. J. Biol. Chem. 283: Identification of apoptosis-related PLZF target genes. Biochem. Biophys. Res. 22565–22572. Commun. 359: 317–322. 26. Ranuncolo, S. M., J. M. Polo, J. Dierov, M. Singer, T. Kuo, J. Greally, R. Green, 52. Savage, A. K., M. G. Constantinides, J. Han, D. Picard, E. Martin, B. Li, M. Carroll, and A. Melnick. 2007. Bcl-6 mediates the germinal center B cell O. Lantz, and A. Bendelac. 2008. The transcription factor PLZF directs the phenotype and lymphomagenesis through transcriptional repression of the DNA- effector program of the NKT cell lineage. Immunity 29: 391–403. damage sensor ATR. Nat. Immunol. 8: 705–714. 53. Kovalovsky, D., O. U. Uche, S. Eladad, R. M. Hobbs, W. Yi, E. Alonzo, K. Chua, 27. Dent, A. L., A. L. Shaffer, X. Yu, D. Allman, and L. M. Staudt. 1997. Control of M. Eidson, H. J. Kim, J. S. Im, et al. 2008. The BTB-zinc finger transcriptional inflammation, cytokine expression, and germinal center formation by BCL-6. regulator PLZF controls the development of invariant natural killer T cell effector Science 276: 589–592. functions. Nat. Immunol. 9: 1055–1064. 28. Ye, B. H., G. Cattoretti, Q. Shen, J. Zhang, N. Hawe, R. de Waard, C. Leung, 54. Raberger, J., A. Schebesta, S. Sakaguchi, N. Boucheron, K. E. Blomberg, M. Nouri-Shirazi, A. Orazi, R. S. Chaganti, et al. 1997. The BCL-6 proto- A. Berglo¨f, T. Kolbe, C. I. Smith, T. Ru¨licke, and W. Ellmeier. 2008. The oncogene controls germinal-centre formation and Th2-type inflammation. transcriptional regulator PLZF induces the development of CD44 high memory Nat. Genet. 16: 161–170. phenotype T cells. Proc. Natl. Acad. Sci. USA 105: 17919–17924. 29. Fukuda, T., T. Yoshida, S. Okada, M. Hatano, T. Miki, K. Ishibashi, S. Okabe, 55. Kovalovsky, D., E. S. Alonzo, O. U. Uche, M. Eidson, K. E. Nichols, and H. Koseki, S. Hirosawa, M. Taniguchi, et al. 1997. Disruption of the Bcl6 gene D. B. Sant’Angelo. 2010. PLZF induces the spontaneous acquisition of memory/ results in an impaired germinal center formation. J. Exp. Med. 186: 439–448. effector functions in T cells independently of NKT cell-related signals. J. Immunol. 30. Toyama, H., S. Okada, M. Hatano, Y. Takahashi, N. Takeda, H. Ichii, 184: 6746–6755. T. Takemori, Y. Kuroda, and T. Tokuhisa. 2002. Memory B cells without somatic 56. Kreslavsky, T., A. K. Savage, R. Hobbs, F. Gounari, R. Bronson, P. Pereira, hypermutation are generated from Bcl6-deficient B cells. Immunity 17: 329–339. P. P. Pandolfi, A. Bendelac, and H. von Boehmer. 2009. TCR-inducible PLZF 31. Tunyaplin, C., A. L. Shaffer, C. D. Angelin-Duclos, X. Yu, L. M. Staudt, and transcription factor required for innate phenotype of a subset of gammadelta K. L. Calame. 2004. Direct repression of by Bcl-6 inhibits plasmacytic T cells with restricted TCR diversity. Proc. Natl. Acad. Sci. USA 106: 12453–12458. differentiation. J. Immunol. 173: 1158–1165. 57. Alonzo, E. S., R. A. Gottschalk, J. Das, T. Egawa, R. M. Hobbs, P. P. Pandolfi, 32. Shaffer, A. L., X. Yu, Y. He, J. Boldrick, E. P. Chan, and L. M. Staudt. 2000. P. Pereira, K. E. Nichols, G. A. Koretzky, M. S. Jordan, and D. B. Sant’Angelo. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, 2010. Development of promyelocytic zinc finger and ThPOK-expressing innate and cell cycle control. Immunity 13: 199–212. gamma delta T cells is controlled by strength of TCR signaling and Id3. 33. Crotty, S., R. J. Johnston, and S. P. Schoenberger. 2010. Effectors and memories: J. Immunol. 184: 1268–1279. Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat. Immunol. 58. Verykokakis, M., M. D. Boos, A. Bendelac, E. J. Adams, P. Pereira, and B. L. Kee. 11: 114–120. 2010. Inhibitor of DNA binding 3 limits development of murine slam-associated 34. Duy, C., J. J. Yu, R. Nahar, S. Swaminathan, S. M. Kweon, J. M. Polo, E. Valls, adaptor protein-dependent “innate” gammadelta T cells. PLoS ONE 5: e9303. L. Klemm, S. Shojaee, L. Cerchietti, et al. 2010. BCL6 is critical for the de- 59. Felices, M., C. C. Yin, Y. Kosaka, J. Kang, and L. J. Berg. 2009. Tec kinase velopment of a diverse primary B cell repertoire. J. Exp. Med. 207: 1209–1221. Itk in gammadeltaT cells is pivotal for controlling IgE production in vivo. 35. Hartatik, T., S. Okada, S. Okabe, M. Arima, M. Hatano, and T. Tokuhisa. 2001. Proc. Natl. Acad. Sci. USA 106: 8308–8313. Binding of BAZF and Bc16 to STAT6-binding DNA sequences. Biochem. Biophys. 60. Fukuyama, T., L. H. Kasper, F. Boussouar, T. Jeevan, J. van Deursen, and Res. Commun. 284: 26–32. P. K. Brindle. 2009. Histone acetyltransferase CBP is vital to demarcate conven- 36. Arima, M., H. Toyama, H. Ichii, S. Kojima, S. Okada, M. Hatano, G. Cheng, tional and innate CD8+ T-cell development. Mol. Cell. Biol. 29: 3894–3904. M. Kubo, T. Fukuda, and T. Tokuhisa. 2002. A putative silencer element in the 61. Weinreich, M. A., O. A. Odumade, S. C. Jameson, and K. A. Hogquist. 2010. IL-5 gene recognized by Bcl6. J. Immunol. 169: 829–836. T cells expressing the transcription factor PLZF regulate the development 37. Yu, D., S. Rao, L. M. Tsai, S. K. Lee, Y. He, E. L. Sutcliffe, M. Srivastava, of memory-like CD8+ T cells. Nat. Immunol. 11: 709–716. M. Linterman, L. Zheng, N. Simpson, et al. 2009. The transcriptional repressor 62. Lee, Y. J., Y. K. Jeon, B. H. Kang, D. H. Chung, C. G. Park, H. Y. Shin, Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31: 457–468. K. C. Jung, and S. H. Park. 2010. Generation of PLZF+ CD4+ T cells via MHC The Journal of Immunology 2847

class II-dependent thymocyte-thymocyte interaction is a physiological process in regulates TH2-driven allergic airway inflammation and airway hyperrespon- humans. J. Exp. Med. 207: 237–246. siveness. J. Allergy Clin. Immunol. 122: 512–520. 63. Xu, D., M. Holko, A. J. Sadler, B. Scott, S. Higashiyama, W. Berkofsky-Fessler, 84. Hirasaki, Y., C. Iwamura, M. Yamashita, T. Ito, M. Kitajima, K. Shinoda, M. J. McConnell, P. P. Pandolfi, J. D. Licht, and B. R. Williams. 2009. Pro- T. Namiki, K. Terasawa, and T. Nakayama. 2011. Repressor of GATA negatively myelocytic leukemia zinc finger protein regulates interferon-mediated innate regulates murine contact hypersensitivity through the inhibition of type-2 allergic immunity. Immunity 30: 802–816. responses. Clin. Immunol. 139: 267–276. 64. Sun, G., X. Liu, P. Mercado, S. R. Jenkinson, M. Kypriotou, L. Feigenbaum, 85. Herna´ndez-Hoyos, G., M. K. Anderson, C. Wang, E. V. Rothenberg, and P. Gale´ra, and R. Bosselut. 2005. The zinc finger protein cKrox directs CD4 J. Alberola-Ila. 2003. GATA-3 expression is controlled by TCR signals and reg- lineage differentiation during intrathymic T cell positive selection. Nat. Immunol. ulates CD4/CD8 differentiation. Immunity 19: 83–94. 6: 373–381. 86. Takamori, M., M. Hatano, M. Arima, A. Sakamoto, L. Fujimura, T. Hartatik, 65. He, X., X. He, V. P. Dave, Y. Zhang, X. Hua, E. Nicolas, W. Xu, B. A. Roe, and T. Kuriyama, and T. Tokuhisa. 2004. BAZF is required for activation of naive D. J. Kappes. 2005. The zinc finger transcription factor Th-POK regulates CD4 CD4 T cells by TCR triggering. Int. Immunol. 16: 1439–1449. versus CD8 T-cell lineage commitment. Nature 433: 826–833. 87. Broxmeyer, H. E., S. Sehra, S. Cooper, L. M. Toney, S. Kusam, J. J. Aloor, 66. Muroi, S., Y. Naoe, C. Miyamoto, K. Akiyama, T. Ikawa, K. Masuda, C. C. Marchal, M. C. Dinauer, and A. L. Dent. 2007. Aberrant regulation of H. Kawamoto, and I. Taniuchi. 2008. Cascading suppression of transcriptional hematopoiesis by T cells in BAZF-deficient mice. Mol. Cell. Biol. 27: 5275– silencers by ThPOK seals helper T cell fate. Nat. Immunol. 9: 1113–1121. 5285. 67. Wang, L., K. F. Wildt, J. Zhu, X. Zhang, L. Feigenbaum, L. Tessarollo, 88. Manders, P. M., P. J. Hunter, A. I. Telaranta, J. M. Carr, J. L. Marshall, W. E. Paul, B. J. Fowlkes, and R. Bosselut. 2008. Distinct functions for the M. Carrasco, Y. Murakami, M. J. Palmowski, V. Cerundolo, S. M. Kaech, et al. transcription factors GATA-3 and ThPOK during intrathymic differentiation 2005. BCL6b mediates the enhanced magnitude of the secondary response of of CD4(+) T cells. Nat. Immunol. 9: 1122–1130. memory CD8+ T lymphocytes. Proc. Natl. Acad. Sci. USA 102: 7418–7425. 68. van Hamburg, J. P., M. J. de Bruijn, C. Ribeiro de Almeida, G. M. Dingjan, and 89. Kobayashi, A., H. Yamagiwa, H. Hoshino, A. Muto, K. Sato, M. Morita, R. W. Hendriks. 2009. Gene expression profiling in mice with enforced Gata3 N. Hayashi, M. Yamamoto, and K. Igarashi. 2000. A combinatorial code for gene expression reveals putative targets of Gata3 in double positive thymocytes. expression generated by transcription factor Bach2 and MAZR (MAZ-related Mol. Immunol. 46: 3251–3260. factor) through the BTB/POZ domain. Mol. Cell. Biol. 20: 1733–1746. 69. He, X., K. Park, H. Wang, X. He, Y. Zhang, X. Hua, Y. Li, and D. J. Kappes. 90. Bilic, I., C. Koesters, B. Unger, M. Sekimata, A. Hertweck, R. Maschek, 2008. CD4-CD8 lineage commitment is regulated by a silencer element at the C. B. Wilson, and W. Ellmeier. 2006. Negative regulation of CD8 expression via ThPOK transcription-factor locus. Immunity 28: 346–358. Cd8 enhancer-mediated recruitment of the zinc finger protein MAZR. Downloaded from 70. Cruz-Guilloty, F., M. E. Pipkin, I. M. Djuretic, D. Levanon, J. Lotem, Nat. Immunol. 7: 392–400. M. G. Lichtenheld, Y. Groner, and A. Rao. 2009. Runx3 and T-box proteins 91. Sakaguchi, S., M. Hombauer, I. Bilic, Y. Naoe, A. Schebesta, I. Taniuchi, and cooperate to establish the transcriptional program of effector CTLs. J. Exp. Med. W. Ellmeier. 2010. The zinc-finger protein MAZR is part of the transcription 206: 51–59. factor network that controls the CD4 versus CD8 lineage fate of double-positive 71. Hu, J., Q. Qi, and A. August. 2010. Itk derived signals regulate the expression of thymocytes. Nat. Immunol. 11: 442–448. Th-POK and controls the development of CD4 T cells. PLoS ONE 5: e8891. 92. Zhao, Z. H., S. F. Wang, L. Yu, J. Wang, H. Chang, W. L. Yan, J. Zhang, and 72. Liu, X., B. J. Taylor, G. Sun, and R. Bosselut. 2005. Analyzing expression K. Fu. 2008. Overexpression of Pokemon in non-small cell lung cancer

of perforin, Runx3, and Thpok genes during positive selection reveals activation and foreshowing tumor biological behavior as well as clinical results. Lung Cancer http://www.jimmunol.org/ of CD8-differentiation programs by MHC II-signaled thymocytes. J. Immunol. 62: 113–119. 175: 4465–4474. 93. Maeda, T., R. M. Hobbs, T. Merghoub, I. Guernah, A. Zelent, C. Cordon-Cardo, 73. Setoguchi, R., M. Tachibana, Y. Naoe, S. Muroi, K. Akiyama, C. Tezuka, J. Teruya-Feldstein, and P. P. Pandolfi. 2005. Role of the proto-oncogene Poke- T. Okuda, and I. Taniuchi. 2008. Repression of the transcription factor Th-POK mon in cellular transformation and ARF repression. Nature 433: 278–285. by Runx complexes in cytotoxic T cell development. Science 319: 822–825. 94. Zu, X., J. Ma, H. Liu, F. Liu, C. Tan, L. Yu, J. Wang, Z. Xie, D. Cao, and 74. Egawa, T., and D. R. Littman. 2008. ThPOK acts late in specification of the Y. Jiang. 2011. Pro-oncogene Pokemon promotes breast cancer progression helper T cell lineage and suppresses Runx-mediated commitment to the cytotoxic by upregulating survivin expression. Breast Cancer Res. 13: R26. T cell lineage. Nat. Immunol. 9: 1131–1139. 95. Maeda, T., T. Merghoub, R. M. Hobbs, L. Dong, M. Maeda, J. Zakrzewski, 75. Setoguchi, R., I. Taniuchi, and M. J. Bevan. 2009. ThPOK derepression is M. R. van den Brink, A. Zelent, H. Shigematsu, K. Akashi, et al. 2007. Regulation required for robust CD8 T cell responses to viral infection. J. Immunol. 183: of B versus T lymphoid lineage fate decision by the proto-oncogene LRF. Science 4467–4474. 316: 860–866.

76. Wang, L., T. Carr, Y. Xiong, K. F. Wildt, J. Zhu, L. Feigenbaum, A. Bendelac, 96. Saba, I., C. Kosan, L. Vassen, and T. Mo¨ro¨y. 2011. IL-7R-dependent survival and by guest on October 2, 2021 and R. Bosselut. 2010. The sequential activity of Gata3 and Thpok is required differentiation of early T-lineage progenitors is regulated by the BTB/POZ domain for the differentiation of CD1d-restricted CD4+ NKT cells. Eur. J. Immunol. 40: transcription factor Miz-1. Blood 117: 3370–3381. 2385–2390. 97. Kosan, C., I. Saba, M. Godmann, S. Herold, B. Herkert, M. Eilers, and T. Mo¨ro¨y. 77. Park, K., X. He, H. O. Lee, X. Hua, Y. Li, D. Wiest, and D. J. Kappes. 2010. 2010. Transcription factor miz-1 is required to regulate interleukin-7 receptor TCR-mediated ThPOK induction promotes development of mature (CD24-) signaling at early commitment stages of B cell differentiation. Immunity 33: gammadelta thymocytes. EMBO J. 29: 2329–2341. 917–928. 78. Engel, I., K. Hammond, B. A. Sullivan, X. He, I. Taniuchi, D. Kappes, and 98. Guidez, F., L. Howell, M. Isalan, M. Cebrat, R. M. Alani, S. Ivins, I. Hormaeche, M. Kronenberg. 2010. Co-receptor choice by V alpha14i NKT cells is driven by M. J. McConnell, S. Pierce, P. A. Cole, et al. 2005. Histone acetyltransferase Th-POK expression rather than avoidance of CD8-mediated negative selection. activity of p300 is required for transcriptional repression by the promyelocytic J. Exp. Med. 207: 1015–1029. leukemia zinc finger protein. Mol. Cell. Biol. 25: 5552–5566. 79. Dai, M. S., N. Chevallier, S. Stone, M. C. Heinrich, M. McConnell, T. Reuter, 99. Kang, S. I., H. W. Choi, and I. Y. Kim. 2008. Redox-mediated modification H. E. Broxmeyer, J. D. Licht, L. Lu, and M. E. Hoatlin. 2002. The effects of the of PLZF by SUMO-1 and ubiquitin. Biochem. Biophys. Res. Commun. 369: Fanconi anemia zinc finger (FAZF) on cell cycle, apoptosis, and proliferation are 1209–1214. differentiation stage-specific. J. Biol. Chem. 277: 26327–26334. 100. Kang, S. I., W. J. Chang, S. G. Cho, and I. Y. Kim. 2003. Modification of 80. Piazza, F., J. A. Costoya, T. Merghoub, R. M. Hobbs, and P. P. Pandolfi. 2004. promyelocytic leukemia zinc finger protein (PLZF) by SUMO-1 conjugation Disruption of PLZP in mice leads to increased T-lymphocyte proliferation, cytokine regulates its transcriptional repressor activity. J. Biol. Chem. 278: 51479– production, and altered hematopoietic stem cell homeostasis. Mol. Cell. Biol. 51483. 24: 10456–10469. 101. Zhang, M., J. Zhang, J. Rui, and X. Liu. 2010. p300-mediated acetylation 81. Miaw, S. C., A. Choi, E. Yu, H. Kishikawa, and I. C. Ho. 2000. ROG, repressor stabilizes the Th-inducing POK factor. J. Immunol. 185: 3960–3969. of GATA, regulates the expression of cytokine genes. Immunity 12: 323–333. 102. Costoya, J. A., R. M. Hobbs, and P. P. Pandolfi. 2008. Cyclin-dependent kinase 82. Kang, B. Y., S. C. Miaw, and I. C. Ho. 2005. ROG negatively regulates T-cell antagonizes promyelocytic leukemia zinc-finger through phosphorylation. activation but is dispensable for Th-cell differentiation. Mol. Cell. Biol. 25: Oncogene 27: 3789–3796. 554–562. 103. Phan, R. T., M. Saito, Y. Kitagawa, A. R. Means, and R. Dalla-Favera. 2007. 83. Hirahara, K., M. Yamashita, C. Iwamura, K. Shinoda, A. Hasegawa, Genotoxic stress regulates expression of the proto-oncogene Bcl6 in germinal H. Yoshizawa, H. Koseki, F. Gejyo, and T. Nakayama. 2008. Repressor of GATA center B cells. Nat. Immunol. 8: 1132–1139.