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Critical roles of Bcl11b in T-cell development and maintenance of T-cell identity. Immunol Rev
ARTICLE in IMMUNOLOGICAL REVIEWS · NOVEMBER 2010 Impact Factor: 10.12 · DOI: 10.1111/j.1600-065X.2010.00953.x · Source: PubMed
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Available from: Peng Li Retrieved on: 14 December 2015 Pentao Liu Critical roles of Bcl11b in T-cell Peng Li development and maintenance of Shannon Burke T-cell identity
Authors’ address Summary: T-cell development primarily occurs in the thymus and 1 1 1 Pentao Liu , Peng Li , Shannon Burke involves in the interactions of many important transcription factors. Until 1 Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. recently, no single transcription factor has been identified to be essential for T-cell lineage commitment or maintenance of T-cell identity. Recent Correspondence to: studies have now identified the zinc finger transcription factor Bcl11b to Pentao Liu be essential for T-cell development and for maintenance of T-cell iden- Wellcome Trust Sanger Institute tity. Remarkably, T cells acquire NK cell properties upon Bcl11b deletion. Hinxton These reprogrammed cells have unique properties in proliferation, cyto- Cambridge, CB10 1HH kine dependency and killing target cells, and may therefore provide a UK new cell source for some cell-based therapies. Tel.: +44 1223496850 Fax: +44 1223496802 Keywords: Bcl11b, T cells, transcription factor, identity, natural killer, reprogramming, e-mail: [email protected] immunotherapy
Introduction The Bcl11 family has two members, Bcl11a and Bcl11b, both being Kruppel-like C2H2 type zinc finger transcription factors (1). Bcl11a was first discovered as a retroviral insertion site (Evi9) in myeloid leukemia tumors in the BXH-2 mouse (2, 3). Evi9 was later renamed as Bcl11a, since it was found ectopi- cally expressed in some B-cell lymphomas caused by chromo- somal translocations (1). Bcl11a is required for normal lymphoid development. Germline deletion of Bcl11a causes neonatal lethality and an absence of B cells at the earliest B-cell development stages (4). Surprisingly, Bcl11a deficiency also causes abnormal T-cell development. Recipient mice of Bcl11a- deficient fetal liver cells develop T-cell leukemia, suggesting that Bcl11a might have important functions in T-cell progeni- tors, since it is expressed in these cells (4–6). Recent genome- wide association studies in human have revealed association of the BCL11A locus with persistent fetal hemoglobin in the adult (7, 8). In the subsequent validation assays, knocking down BCL11A in human primary adult erythroid cells indeed Immunological Reviews 2010 leads to robust HbF expression (9). Further characterization of Vol. 238: 138–149 Printed in Singapore. All rights reserved Bcl11a mutant mice also uncovers the key role of Bcl11a in the fetal-to-adult expression switch of hemoglobin (9, 10). 2010 John Wiley & Sons A/S Immunological Reviews Recent studies demonstrate that Klf1 positively regulates 0105-2896 Bcl11a in this process (11, 12).
138 2010 John Wiley & Sons A/S • Immunological Reviews 238/2010 Liu et al Æ Bcl11b has essential functions in T cells
Bcl11b is the other member of the Bcl11 family in the mouse transcription has been identified for T-cell lineage commit- and human genomes. The Bcl11b locus was once named Rit1 ment and ⁄ or identity maintenance. (radiation-induced tumor suppressor gene 1), because homozygous Gene expression analysis in thymocytes reveals that Bcl11b deletions and point mutations were located to this locus in a is the most upregulated transcription factor at the transition genome-wide allelic loss analysis of c-ray induced mouse thy- from DN1 to DN2, suggesting the potential function of mic lymphomas (13–15). Therefore, Bcl11b was initially Bcl11b in early T-cell development and its possible connection identified as a tumor suppressor in T cells. with Notch signaling (6, 42). This review summarizes recent T-cell development takes place in the thymus. The earliest studies that identify Bcl11b as the key factor required for populations of progenitor thymocytes lack T-cell receptor T-cell lineage commitment and for the maintenance of (TCR) coreceptors CD4 and CD8, and are therefore referred T-cell identity. as double negative (DN) cells (16). The DN population can be further subdivided by cell surface markers CD117 (c- ) Kit), CD44, and CD25 (17). The DN1 (CD44+CD25 ) pop- Bcl11b is specifically expressed in T cells ulation of progenitor thymocytes are thought to contain Bcl11b is highly expressed in mouse and human T lympho- multipotent progenitors (18–22). Although NK and myeloid cytes (43, 44). During evolution, a homolog of Bcl11b first potentials persist in DN2 cells (CD44+CD25+) (21, 22), the appears in cartilaginous fishes. In sea lampreys, a jawless ver- non-T-cell developmental potentials are lost in the DN3 tebrate, specific expression of a Bcl11b ortholog is detected in ) ) ) (CD44 CD25+) thymocytes. DN4 thymocytes (CD44 CD25 ) VLRA+ cells that are similar to T lymphocytes in vertebrates, have undergone b-selection after successful TCRb gene rear- but not in VLRB+ cells that are similar to B lymphocytes (45). rangement (23) and have already initiated the process of dif- In bony fish, the Bcl11b ortholog is expressed in the thymus ferentiating to the CD4+CD8+ double positive (DP) stage and positively regulates Ccr9 (46), which encodes the receptor (24, 25). Once thymocytes survive the positive and negative for ccl25, a novel chemokine. Both Ccr9 and Ccl25 are now selection processes, they migrate to the peripheral lymphoid shown to have important functions in the recruitment of pro- tissues where the cytokine interleukin-7 (IL-7) and the con- genitors to the thymus and early thymocyte development (47, stant interaction of T cells with self-peptide-major histo- 48). compatibility complex (MHC) play a critical role in T-cell Bcl11b expression has been characterized at the single cell homeostasis (26). level in a reporter knockin mouse where the Td-Tomato cassette T-cell development requires a complex interplay among key is targeted to the 3¢ untranslated region (UTR) of the Bcl11b transcription factors with Notch signaling playing a critical locus (5). In hematopoietic lineages, Bc11b expression is role (27). Notch triggers initiation of the T-cell program, and strictly T-cell restricted with transient low levels expression in is required to sustain the cells throughout the pro-T-cell stages some immature natural killer (NK) cells. In the mouse thy- (28–30). Loss of Notch signaling in DN1 cell converts them mus, it is expressed at high levels throughout T-cell develop- into DCs (31). Deletion of Notch1 in the thymus leads to accu- ment including almost all DN2-DN4 and DP thymocytes, mulation of B cells in the thymus, possibly by a cell-extrinsic CD4+ and CD8+ single positive T cells, cd T cells, and natural pathway (28, 31). In committed T cells, Notch signaling killer T (NKT) cells. However, early T-cell-lineage progenitors favors ab versus cd T-cell lineage (32, 33), influences CD4+ (ETP), defined as CD117++DN1 thymocytes (27), did not versus CD8+ lineage decisions (34) and affects T-helper devel- express Bcl11b (5). Indeed, Bcl11b expression is undetectable opment partly through Gata3 (35, 36). in all other thymocytes that express CD117, such as some Other transcription factors that are essential for various T- DN2 thymocytes (5), suggesting that Bcl11b might suppress cell subtypes are also characterized. For example, zinc finger expression of c-kit (CD117), which is often found in progeni- transcription factor Th-POK (Zbtb7b), which appears to be tors. repressed by Runx complexes (37), regulates CD4+ versus In peripheral mature T cells, Bcl11b is expressed in both CD8+ T-cell lineage commitment (38). T-bet (Tbx21), a CD4+ and CD8+ T cells with lower levels of Bcl11b expression T-box transcription factor, directs T-helper 1 (Th1) lineage in CD8+ T cells. Interestingly, some activated T cells ) commitment (39). Gata3 is necessary and sufficient for Th2 (CD44+CD62L ) express very low levels of Bcl11b (5), sug- cytokine gene expression in CD4+ T cells (40). Eomesoder- gesting that it might have functions in TCR signaling, perhaps min, another T-box transcription factor, controls effector normally suppressing some activation-associated genes thus CD8+ T-cell function (41). Despite these advances, no single inhibiting T-cell activation. The specific and dynamic expres-