The Multifaceted Roles of Bcl11b in Thymic and Peripheral T Cells: Impact on Immune Diseases This information is current as Dorina Avram and Danielle Califano of September 29, 2021. J Immunol 2014; 193:2059-2065; ; doi: 10.4049/jimmunol.1400930 http://www.jimmunol.org/content/193/5/2059 Downloaded from References This article cites 61 articles, 30 of which you can access for free at: http://www.jimmunol.org/content/193/5/2059.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 *average by guest on September 29, 2021 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 © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology The Multifaceted Roles of Bcl11b in Thymic and Peripheral T Cells: Impact on Immune Diseases Dorina Avram and Danielle Califano The transcription factor Bcl11b is expressed in all T cell T cell commitment at the DN2 stage (16, 25, 26), survival of subsets and progenitors, starting from the DN2 stage of DN3 and double-positive (DP) thymocytes (18, 27), b se- T cell development, and it regulates critical processes lection at the DN3 stage, positive selection of CD4 and CD8 implicated in the development, function, and survival single-positive (SP) thymocytes (18, 27, 28), development of of many of these cells. Among the common roles of Treg cells (22) and iNKT cells (23), and, most recently, de- Bcl11b in T cell progenitors and mature T cell subsets velopment of a subpopulation of gd T cells (29). In mature are the repression of the innate genetic program and, to T cells, Bcl11b was demonstrated to control expansion and some extent, expression maintenance of TCR-signaling effector function of CTLs (19), restrict plasticity of Th17 cells Downloaded from components. However, Bcl11b also has unique roles in by blocking expression of the Th2 program (21), control generation of inducible Treg (iTreg) cells from conventional specific T cell populations, suggesting that its functions + depend on cell type and activation state of the cell. In this CD4 T cells, and, overall, to control the suppression func- article, we provide a comprehensive review of the roles of tion of Treg cells (22). Dissecting the roles of Bcl11b in different cellular contexts and Bcl11b in progenitors, effector T cells, regulatory T cells, the factors that regulate Bcl11b provides valuable information for http://www.jimmunol.org/ and invariant NKT cells, as well as its impact on im- the growing transcriptional networks that involve Bcl11b, as well mune diseases. While emphasizing common themes, as for its implications in immune diseases. Furthermore, as new including some that might be extended to skin and neu- populations of immune cells are identified, such as innate lym- rons, we also describe the control of specific functions phoid cells, novel Bcl11b targets and functions may be discovered. in different T cell subsets. The Journal of Immunology, 2014, 193: 2059–2065. Bcl11b is essential for multiple checkpoints during T cell development Bcl11b in early stages of T cell development: repression of multi-potency cl11b was initially discovered in neurons as CTIP2, and alternate lineage potential and enforcement of commitment. The by guest on September 29, 2021 along with its family member CTIP1 or Bcl11a (1), development of T cells is a multi-step process that requires B and it was later demonstrated to be critical for the environmental cues, including Notch signaling and cytokines, proper development and function of neurons (2–5). Bcl11b is expression of key transcription factors necessary for T cell com- mitment, and downregulation of factors that support multi- aC2H2 zinc finger protein that binds GC-rich response elements (6), and it was described to associate with a variety of cofactors, potency and alternative lineages. Ellen Rothenberg’s group (14, 17, 25) showed that Bcl11b expression is initiated at the including the corepressor complexes NuRD (7, 8) and Sirt1 (9), as DN2a stage and continues to increase, reaching a peak at the well as with the histone acetyltransferase (HAT) p300 (10), func- DN2b stage, when self-renewal and multi-potency are sup- tioning both as a transcriptional repressor and activator (1, 6–13). pressed. Using the OP-DL1 system, they demonstrated ex vivo Bcl11b expression is initiated in a Notch1- and TCF-1– that the absence of Bcl11b caused accumulation of DN1- and dependent manner at the double-negative (DN)2 stage of DN2a-stage thymocytes that expressed myeloid and NK lineage T cell development (14–17) and is maintained in mature genes and failed to shut off stem cell and multi-potency genes T lymphocytes, including invariant NKT (iNKT) cells and (25) (Fig. 1). At the same time, Pentao Liu’s group (16) demon- regulatory T (Treg) cells (16, 18–23). It is expressed at lower strated that the loss of Bcl11b ex vivo caused reprogramming of levels in NK cells, but not in B cells, myeloid cells, or den- DN2, DN3, and DP thymocytes to NK-like cells, designated dritic cells (16, 18, 20). In addition, Bcl11b was identified as a induced T-to-NK (ITNK), which upregulated NK lineage radiation-induced tumor suppressor gene, Rit1,inp53+ thymic genes, such as Id2, NK1.1, and NKp46, and possessed increased lymphomas (24). Years of in-depth study revealed that Bcl11b antitumor activity (see below). In a parallel study, Hiroshi is necessary for several developmental checkpoints, including Kawamoto’s group (26), despite earlier reports of a developmental Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY Abbreviations used in this article: DN, double negative; DP, double positive; EAE, 12208 experimental autoimmune encephalomyelitis; HAT, histone acetyltransferase; IBD, in- flammatory bowel disease; iNKT, invariant NKT; ITNK, induced T-to-NK; iTreg, in- Received for publication April 10, 2014. Accepted for publication June 25, 2014. ducible Treg; nTreg, thymic-derived or natural Treg; RA, retinoic acid; SP, single positive; This work was supported by National Institute of Allergy and Infectious Diseases, Treg, regulatory T. National institutes of Health Grants AI067846 and AI078273 (to D.A.). Ó Address correspondence and reprint requests to Dr. Dorina Avram, Center for Immu- Copyright 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 nology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400930 2060 BRIEF REVIEWS: Bcl11b IN T CELLS AND IMMUNE DISEASES 2 2 block at the DN3 stage in global Bcl11b / mice (27) (see below), of Bcl11b, in which the Cre recombinase expression accu- concluded that the developmental block is rather at the DN2 stage mulates at the DP stage, was used to elucidate the role of (26). Despite the developmental block, the absolute numbers of Bcl11b in DP thymocytes (18, 28). We showed that these 2 2 Bcl11b / DN2 thymocytes were not increased, although they mice had a significant reduction in CD4 and CD8 SP thy- vigorously proliferated and differentiated to NK and myeloid cells mocytes and peripheral CD4+ and CD8+ T cells, concomitant ex vivo (26), similar to what was reported in the other two studies with an increase in some immune cell populations, including NK (16, 25). Thus, these three studies all point to a critical role for and myeloid cells. The increase in NK and myeloid cell numbers Bcl11b at the DN2 stage in controlling the expression of genes was associated with elevated splenic and bone marrow that support T cell commitment and suppress multi-potency and hematopoiesis through a bystander mechanism mediated by alternative lineage genes (Fig. 1). It remains to be established TNF-a, without indication of increased expansion (18, 31) 2/2 whether Bcl11b DN2 thymocytes generated in vivo remain (see below). The elevation in other immune populations, blocked at DN2 stage or differentiate into NK and myeloid cells. including B cells and gd T cells, could be attributed to in- Bcl11b at DN3 stage and b selection. As thymocytes enter the creased hematopoiesis and/or homeostatic expansion (18, 31). DN3 stage, TCR rearrangements occur at the TCRb locus. The reduction in peripheral T cells was caused by defective Ryo Kominami’s group (27) analyzed neonatal thymi of positive selection, associated with impaired TCR signaling (18) 2 2 2 2 global Bcl11b / mice, which die soon after birth as a result (Fig. 1). Although TCRa was normally rearranged, Bcl11b / of neuronal defects, and showed that thymocyte development DP thymocytes had increased spontaneous apoptosis, which 2 2 was blocked at the DN3 stage, concomitant with diminished occurredevenintheabsenceofTCRsignaling,onaTCRa / Downloaded from cellularity and increased apoptosis (Fig. 1). Additionally, background (18). A slight decrease in the Bcl2 family member TCRb mRNA and protein levels were reduced as a result of BCLXL and an increase in proapoptotic factors was observed; impaired Vb to Db rearrangements (27), restricting formation however, provision of the prosurvival factor Bcl2 only partially of the pre-TCR and halting T cell development. Provision rescued survival, suggesting that additional factors are implicated of a transgenic TCR only partially rescued the defect (30), (see below).