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CD8 T Cell Memory Transition and Maintenance of Functional Foxo1 FoxO1 Controls Effector-to-Memory Transition and Maintenance of Functional CD8 T Cell Memory This information is current as Melba Marie Tejera, Eui Ho Kim, Jeremy A. Sullivan, Erin of October 1, 2021. H. Plisch and M. Suresh J Immunol 2013; 191:187-199; Prepublished online 3 June 2013; doi: 10.4049/jimmunol.1300331 http://www.jimmunol.org/content/191/1/187 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2013/06/03/jimmunol.130033 Material 1.DC1 http://www.jimmunol.org/ References This article cites 52 articles, 7 of which you can access for free at: http://www.jimmunol.org/content/191/1/187.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 1, 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 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 FoxO1 Controls Effector-to-Memory Transition and Maintenance of Functional CD8 T Cell Memory Melba Marie Tejera, Eui Ho Kim, Jeremy A. Sullivan, Erin H. Plisch, and M. Suresh During a T cell response, naive CD8 T cells differentiate into effector cells. Subsequently, a subset of effector cells termed memory precursor effector cells further differentiates into functionally mature memory CD8 T cells. The transcriptional network underlying this carefully scripted process is not well understood. In this study, we report that the transcription factor FoxO1 plays an integral role in facilitating effector-to-memory transition and functional maturation of memory CD4 and CD8 T cells. We find that FoxO1 is not required for differentiation of effector cells, but in the absence of FoxO1, memory CD8 T cells displayed features of senescence and progressive attrition in polyfunctionality, which in turn led to impaired recall responses and poor protective immunity. These data suggest that FoxO1 is essential for maintenance of functional CD8 T cell memory and protective immunity. Under competing Downloaded from conditions in bone marrow chimeric mice, FoxO1 deficiency did not perturb clonal expansion or effector differentiation. Instead, FoxO1-deficient memory precursor effector cells failed to survive and form memory CD8 T cells. Mechanistically, FoxO1 deficiency perturbed the memory CD8 T cell transcriptome, characterized by pronounced alterations in the expression of genes that encode transcription factors (including Tcf7), effector molecules, cell cycle regulators, and proteins that regulate fatty acid, purine, and pyramidine metabolism and mitochondrial functions. We propose that FoxO1 is a key regulator that reprograms and steers the differentiation of effector cells to functionally competent memory cells. These findings have provided fundamental insights into the http://www.jimmunol.org/ mechanisms that regulate the quality of CD8 T cell memory to intracellular pathogens. The Journal of Immunology, 2013, 191: 187–199. uring T cell responses to vaccines or infections, TCR velopmental pathway from naive T cells to fully functional signaling occurring in concert with costimulatory and memory CD8 T cells encompasses two critical differentiation D inflammatory signals stimulate naive CD8 T cells to checkpoints. First is the differentiation of naive T cells to effector clonally expand and differentiate into effector CD8 T cells (1, 2). cells, and second is the differentiation of effector cells to functional memory CD8 T cells (3). The generation of a protective population The resulting heterogeneous population of effector cells consists by guest on October 1, 2021 of at least two subsets: the terminally differentiated short-lived of memory T cells depends on successful passage through both effector cells (SLECs) and memory precursor effector cells checkpoints; therefore, a thorough understanding of the cellular (MPECs) (3). Upon resolution of the insult, the majority of the processes underlying these transitions is necessary for the rational SLECs are lost by apoptosis, but MPECs survive and eventually development of strategies to manipulate CD8 T cell memory. differentiate into long-lived memory CD8 T cells. Upon reinfec- The differentiation to effector cells from naive T cells is asso- tion, memory CD8 T cells rapidly expand and/or develop effector ciated with installation of the effector transcription program driven functions to clear the infection expeditiously; this is the basis of by transcription factors such as T-bet and Blimp-1 (5‑8). This CD8 T cell memory-dependent protective immunity (4). The de- transcriptional program transforms quiescent cells into SLECs and MPECs. The subsequent differentiation of the MPECs into mature memory T cells occurs more slowly over a period of several Department of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706 weeks. It is clear that the installation of a memory-specific tran- Received for publication February 1, 2013. Accepted for publication April 24, 2013. scriptional program must encompass substantial changes in gene expression (9). The MPECs, which are present among the effec- This work was supported by Public Health Service grants from the National Institutes of Health (AI48785 and AI101976, to M.S.). M.M.T. was supported by a Virology tors at the peak of the response, do not yet possess the attributes Training Grant from the National Institutes of Health (T32AI078985). that define competent memory CD8 T cells (9). These MPECs The data presented in this article have been submitted to the National Center for lack the ability to self-renew by cytokine-driven proliferation, do Biotechnology Information’s Gene Expression Omnibus (http://www.ncbi.nlm.nih. not proliferate upon re-exposure to the Ag or produce cytokines gov/geo/query/acc.cgi?acc=GSE45673) under accession number GSE45673. such as IL-2, and confer poor protective immunity to reinfection Address correspondence and reprint requests to Dr. M. Suresh, Department of Path- obiological Sciences, University of Wisconsin, 2015 Linden Drive, Madison, WI (9). Essentially, the new transcriptional program must facilitate 53706. E-mail address: [email protected] a transition from a state of cell cycle arrest and highly active The online version of this article contains supplemental material. cytolytic function to a pseudoquiescent state defined by height- Abbreviations used in this article: Bcl-6, B cell lymphoma 6; BMC, bone marrow ened preparedness to rapidly proliferate and/or develop effector cell; CC, control chimera; CD62L, L-selectin; David, Database for Annotation, Vi- functions upon Ag re-exposure (9). Multiple transcription factors sualization and Integrated Discovery; EC, experimental chimera; Gznb, granzyme B; KLRG-1, anti–killer cell lectin-like receptor subfamily G member 1; LCMV, lympho- such as T cell factor 1 (TCF-1) and B cell lymphoma 6 (Bcl-6) cytic choriomeningitis virus; MFI, mean fluorescent intensity; MPEC, memory precursor have been implicated in the regulation of effector-to-memory tran- effector cell; PI, postinfection; SLEC, short-lived effector cell; TCF-1, T cell factor 1; sition (10–12); however, the full transcriptional network governing WT, wild-type. the functional maturation and maintenance of memory CD8 T cells Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 remains poorly defined. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1300331 188 FoxO1 REGULATES T CELL MEMORY In mammals, members of the Forkhead box-O class of tran- Viral infections scription factors collectively referred to as FoxOs include FoxO1, Mice that are 6–8 wk old were infected i.p. with 2 3 105 PFU Armstrong FoxO3, FoxO4, and FoxO6 (13). The FoxOs play a crucial role in strain of lymphocytic choriomeningitis virus (LCMV) to induce acute regulating cellular processes such as proliferation, apoptosis, infection. LCMV-immunized mice were challenged with clone 13 strain of 6 energy metabolism, and stress resistance in response to dynamic LCMV i.v. at a dose of 2 3 10 PFU, and infectious LCMV was quantified alterations in stress and abundance of nutrients and growth factors by a plaque assay on Vero cells, as described previously (30). (14–16). In resting, quiescent cells, FoxOs exist in a hypo- Flow cytometry and cell surface staining phosphorylated state and localize to the nucleus to control the Single-cell suspensions of mononuclear cells from spleen were prepared transcription of target genes that affect cellular proliferation or using standard procedures. MHC class I tetramers, specific for the LCMV apoptosis (17). However, in response to stimulation with growth epitopes Db/NP396-404 and Db/GP33-41, were prepared and used as de- factors or cytokines that stimulate the PI3K/AKT signaling path- scribed previously (31). Briefly, cells were stained with anti-CD8 (53-6.7) way, activated Akt phosphorylates FoxO, leading to its exclusion and MHC class I tetramers. In some experiments, cells were costained with anti-CD44 (IM7), anti–L-selectin (CD62L) (MEL-14), anti–killer cell lectin- from the nucleus and degradation by proteolysis in the cytoplasm like receptor subfamily G member 1 (KLRG-1) (2F1), anti-CD127 (A7R34), (18, 19). Consequently, the transcription of FoxO target genes is anti-CD122 (TM-b 1), anti-CD27 (LG.3A10), anti–LFA-1 (2D7), anti- diminished, which facilitates cell cycle entry. CD45.1 (Ly5.1) (A20), and anti-CD45.2 (Ly5.2) (104). All Abs were T cells express FoxO1 and FoxO3, which play key roles in the purchased from BD Biosciences or eBioscience, except the anti–KLRG-1 maintenance of T cell homeostasis (20, 21).
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