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T Cell Differentiation + Memory CD8 Id2-Mediated Inhibition of E2A

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T Cell Differentiation + Memory CD8 Id2-Mediated Inhibition of E2A Id2-Mediated Inhibition of E2A Represses Memory CD8 + T Cell Differentiation Frederick Masson, Martina Minnich, Moshe Olshansky, Ivan Bilic, Adele M. Mount, Axel Kallies, Terence P. Speed, This information is current as Meinrad Busslinger, Stephen L. Nutt and Gabrielle T. Belz of October 2, 2021. J Immunol 2013; 190:4585-4594; Prepublished online 27 March 2013; doi: 10.4049/jimmunol.1300099 http://www.jimmunol.org/content/190/9/4585 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2013/03/27/jimmunol.130009 Material 9.DC1 References This article cites 34 articles, 8 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/190/9/4585.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 2, 2021 • Fast Publication! 4 weeks from acceptance to publication *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 Author Choice Freely available online through The Journal of Immunology Author Choice option 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 © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Id2-Mediated Inhibition of E2A Represses Memory CD8+ T Cell Differentiation Frederick Masson,* Martina Minnich,† Moshe Olshansky,‡ Ivan Bilic,†,1 Adele M. Mount,†,2 Axel Kallies,*,x Terence P. Speed,‡,{ Meinrad Busslinger,† Stephen L. Nutt,*,x and Gabrielle T. Belz*,x The transcription factor inhibitor of DNA binding (Id)2 modulates T cell fate decisions, but the molecular mechanism underpinning this regulation is unclear. In this study we show that loss of Id2 cripples effector differentiation and instead programs CD8+ T cells to adopt a memory fate with increased Eomesodermin and Tcf7 expression. We demonstrate that Id2 restrains CD8+ T cell memory differentiation by inhibiting E2A-mediated direct activation of Tcf7 and that Id2 expression level mirrors T cell memory recall capacity. As a result of the defective effector differentiation, Id2-deficient CD8+ T cells fail to induce sufficient Tbx21 expression to + generate short-lived effector CD8 T cells. Our findings reveal that the Id2/E2A axis orchestrates T cell differentiation through the Downloaded from induction or repression of downstream transcription factors essential for effector and memory T cell differentiation. The Journal of Immunology, 2013, 190: 4585–4594. uccessful eradication and protection from reinfection by ory CD8+ T cells poised to rapidly respond to a second encounter intracellular pathogens such as viruses and bacteria depend with the pathogen. on the generation of effector and memory CD8+ T cells. Several transcription factors are essential for the specification http://www.jimmunol.org/ S + Naive CD8 T cells, on encounter with dendritic cells presenting and differentiation of peripheral T cells following Ag encounter. pathogen Ags, undergo multiple rounds of proliferation and rap- These include the basic helix-loop-helix proteins inhibitor of DNA idly differentiate into short-lived Ag-specific effector T cells with binding (Id)2 and Id3 (1–3), the T-box transcription factors T-bet cytotoxic and cytokine producing capacity. After resolution of the and eomesodermin (Eomes) (4), B lymphocyte–induced matura- infection, effector CD8+ T cell numbers contract significantly, tion protein 1 (Blimp1) (5–7), Bcl-6 (8), and Tcf7 (also known leaving a small (5–10%) residual population of long-lived mem- as TCF-1) (9). T-bet (encoded by Tbx21) and Blimp1 (encoded by Prdm1) direct the terminal differentiation of effector T cells. Ablation of either T-bet or Blimp1 results in a complete loss of *Division of Molecular Immunology, Walter and Eliza Hall Institute of Medical by guest on October 2, 2021 + low Research, Melbourne, Victoria 3052, Australia; †Research Institute of Molecular KLRG1 IL-7R short-lived effector cells. Furthermore, T-bet ‡ Pathology, Vienna Biocenter, 1030 Vienna, Austria; Division of Bioinformatics, drives effector cell formation in a dose-dependent manner at the Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia; xDepartment of Medical Biology, University of Melbourne, Melbourne, expense of the formation of memory cells (10). Maintenance of Victoria 3010, Australia; and {Department of Mathematics and Statistics, University memory cells appears to depend on the induction of Eomes (4). of Melbourne, Melbourne, Victoria 3010, Australia Although our understanding of Eomes regulation is incomplete, 1 Current address: Akron Molecules GmbH, Vienna, Austria. recent evidence suggests that Tcf7, a critical mediator of the Wnt/ 2Current address: CSL Limited, Parkville, VIC, Australia. b-catenin pathway, regulates CD8+ T cell memory by direct Received for publication January 11, 2013. Accepted for publication February 20, binding to the Eomes locus (9). However, the interactions among 2013. these transcription factors, as well as the signals that drive effector This work was supported by grants and fellowships from the National Health and and memory CD8+ T cell fate decisions, are still poorly understood. Medical Research Council of Australia (to G.T.B., S.L.N., and T.P.S.), the Wellcome Trust (to G.T.B.), the Viertel Foundation and the Howard Hughes Medical Institute It is now established that peripheral T cell differentiation is (to G.T.B.), the Australian Research Council (to T.P.S.), and the Australian Research regulated by the activity of Id proteins (11). Four Id proteins (Id1, Council Future Fellowship (to G.T.B., A.K., and S.L.N.). Research of the Busslinger Id2, Id3, Id4), which lack a DNA-binding domain, are capable of Group was supported by Boehringer Ingelheim and the Genome Research in Austria initiative (financed by the Bundesminsterium fu¨r Bildung und Wissenschaft). This binding the E proteins, E2A (possessing two isoforms, E47 and work was also supported by Victorian State Government operational infrastructure E12), HEB, and E2-2. The recent development of reporter mice support and by the Australian Government National Health and Medical Research Council Independent Research Institute Infrastructure Support Scheme. for Id2 and Id3 has identified that these two transcriptional reg- ulators are expressed in a reciprocal manner and regulate distinct Address correspondence and reprint requests to Dr. Gabrielle T. Belz, Division of Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, 1G functions in the differentiation of peripheral T cells (3). For ex- Royal Parade, Parkville, VIC 3052, Australia. E-mail address: [email protected] ample, Id2 is upregulated in effector T cells. In contrast, induction The online version of this article contains supplemental material. of Id3 reflects the emergence of precursors of long-lived memory Abbreviations used in this article: Blimp1, B lymphocyte–induced maturation protein T cells, and repression by Blimp1 limits formation of memory 1; ChIP, chromatin immunoprecipitation; DE, differentially expressed; Eomes, eome- CD8+ T cells, thus dispelling the notion that Id2 and Id3 are sodermin; Gzm, granzyme; Id, inhibitor of DNA binding; i.n., intranasal(ly); IRES, internal ribosome entry site; Lm-OVA, Listeria monocytogenes encoding OVA; LN, simply redundant (2, 3). lymph node; MSCV, murine stem cell virus; NP, nucleoprotein; PA, acidic polymer- Id2 has multiple essential functions in the hematopoietic sys- ase; shRNA, short hairpin RNA. tem. It is required for the development of CD103+ and CD8a+ den- This article is distributed under The American Association of Immunologists, Inc., dritic cells, NK cells, a subset of intraepithelial T cells, and lym- Reuse Terms and Conditions for Author Choice articles. phoid tissue inducer cells (12, 13). In Ag-specific CD8+ Tcells,Id2 Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 has been proposed to act mainly by regulating their survival during www.jimmunol.org/cgi/doi/10.4049/jimmunol.1300099 4586 Id2 INHIBITS T CELL MEMORY infection (1), but the precise molecular mechanisms downstream BD Pharmingen). Viable cells were analyzed by flow cytometry using of Id2 that determine T cell fate are poorly defined. propidium iodide or Sytox blue exclusion (Invitrogen). Analysis was To understand this pathway in greater depth we generated mice performed on a FACSCanto or a FACS LSRFortessa (BD Biosciences) and data were analyzed using FlowJo flow cytometry analysis software. with a reporter allele encoding GFP under the endogenous Id2 promoter (12) and a conditional allele allowing specific deletion Generation of bone marrow chimeras of Id2 in T cells. This enabled us to examine the cellular and mo- Mixed bone marrow chimeras were established by reconstituting lethally lecular pathway resulting from the loss of Id2 and to explore the irradiated (2 3 0.55 Gy) B6.Ly5.1 or Ly5.1 3 Ly5.2 (F1) recipient mice mechanisms affecting effector and memory T cell fate outcomes with a mixture of Id2fl/flLckCre (3.4 3 106) and wild-type (Ly5.1+, 1.6 3 in an infection setting. We demonstrated that Id2 was essential for 106) T cell–depleted bone marrow cells and allowed to reconstitute for the induction of high levels of Tbx21 and this was required for the 6–8 wk (5, 21). + + generation of short-lived effector CD8 cells. Loss of Id2 in CD8 Microarray analysis T cells impaired effector T cell differentiation and programmed b + + T cells to adopt a memory cell phenotype with increased Eomes D NP366 CD8 T cells were purified by flow cytometric sorting (FAC- SAria flow cytometer; BD Biosciences) from day 9 HKx31-infected PR8- and Tcf7 expression.
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