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Peripheral T Cells Ets-1 Maintains IL-7 Receptor Expression In The Journal of Immunology Ets-1 Maintains IL-7 Receptor Expression in Peripheral T Cells Roland Grenningloh,*,† Tzong-Shyuan Tai,* Nicole Frahm,†,‡,1 Tomoyuki C. Hongo,‡ Adam T. Chicoine,‡ Christian Brander,†,‡,x,{ Daniel E. Kaufmann,†,‡,‖ and I-Cheng Ho*,† The expression of CD127, the IL-7–binding subunit of the IL-7 R, is tightly regulated during the development and activation of T cells and is reduced during chronic viral infection. However, the molecular mechanism regulating the dynamic expression of CD127 is still poorly understood. In this study, we report that the transcription factor Ets-1 is required for maintaining the expression of CD127 in murine peripheral T cells. Ets-1 binds to and activates the CD127 promoter, and its absence leads to reduced CD127 expression, attenuated IL-7 signaling, and impaired IL-7–dependent homeostatic proliferation of T cells. The expression of CD127 and Ets-1 is strongly correlated in human T cells. Both CD127 and Ets-1 expression are decreased in CD8+ T cells during HIV infection. In addition, HIV-associated loss of CD127 is only observed in Ets-1low effector memory and central memory but not in Ets-1high naive CD8+ T cells. Taken together, our data identify Ets-1 as a critical regulator of CD127 expression in T cells. The Journal of Immunology, 2011, 186: 969–976. nterleukin-7 signals are required for T cell development, GABPa or another Ets protein is responsible for maintaining maintaining the naive T cell pool, mounting proper primary CD127 expression in peripheral T cells is unknown. I responses, and inducing and maintaining CD4+ and CD8+ Ets-1 (E26 transformation-specific sequence) is the founding T cell memory (1–3). The IL-7R consists of the IL-7Ra–chain member of the Ets family of transcription factors and is expressed (CD127), which binds IL-7, and the common g-chain (CD132). at high levels in lymphoid cells (8, 11). Ets-1 has been shown to CD127 expression is dynamically regulated throughout T cell promote Th1 and inhibit Th17 differentiation (12, 13). Ets-1 is development, activation, and memory formation (2, 4). Many also recruited to the IL-5/IL-13/IL-4 locus and required for the extracellular stimuli can modulate the expression of CD127. For optimal expression of these cytokines (14). T cells express two example, TCR signals (5), IL-7 (6), and the HIV Tat protein (7) splice variants, the full-length Ets-1 p51 and the shorter Ets-1 p42 have been shown to inhibit the expression of CD127. However, that lacks exon VII (15, 16). The activity of Ets-1 is regulated by the mechanisms governing this dynamic regulation of CD127 are activating and inactivating phosphorylation events (11), but the poorly understood. The constitutive expression of CD127 is reg- role of these phosphorylation events in regulating the function of ulated by members of the Ets family of transcription factors in Th cells remains controversial (17). different lymphoid lineages. Ets proteins are characterized by their In this study, we show that Ets-1 directly binds to and activates the DNA-binding Ets domain (8). The B cell-specific PU.1 is essential CD127 promoter. Ets-1–deficient (KO) T cells expressed reduced for the expression of CD127 in lin2 hematopoietic progenitors and levels of CD127 and displayed impaired IL-7–dependent survival pro-B cells (9), whereas GABPa is required for the expression of and homeostatic proliferation. Importantly, the level of CD127 in CD127 in early thymocytes (10). Both factors bind to a function- human T cells strongly correlates with that of Ets-1. Loss of CD127 ally critical Ets binding site in the CD127 promoter. But whether expression is a hallmark of CD8+ T cells during chronic viral in- fection (18, 19). The expression of Ets-1 is also reduced in CD8+ T cells of HIV-positive individuals mainly due to an expansion of *Division of Rheumatology, Immunology, and Allergy, Department of Medicine, † effector/effector memory cells. Notably, HIV-associated reduction in Brigham and Women’s Hospital, Boston, MA 02115; Harvard Medical School, low Boston, MA 02115; ‡Ragon Institute of MGH, MIT, and Harvard, Charlestown, CD127 occurs only in Ets-1 effector memory and central memory MA 02129; xCatalan Institution for Research and Advanced Studies, Barcelona, cells but not in Ets-1high naive cells. Thus, our data demonstrate that Spain; {AIDS Research Institute Irsicaixa-Catalan HIV Vaccine Program, Hospital ‖ Ets-1 is a critical regulator of CD127 in peripheral T cells. Germans Trias i Pujol, Badalona, Spain; and Infectious Disease Unit, Massachusetts General Hospital, Boston, MA 02114 1Current address: HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Materials and Methods Center, Seattle, WA. Study subjects Received for publication June 25, 2010. Accepted for publication November 9, 2010. This work was supported in part by National Institutes of Health Grant AI081052 (to The study included 10 individuals chronically infected with HIV. Four of I.-C.H.), a Senior Research award from the Crohn’s and Colitis Foundation of America these subjects were treated with antiviral therapy, and six were untreated. (to I.-C.H.), National Institutes of Health Grant HL092565 (to D.E.K.), and a National All but one had plasma viral loads above the limit of detection of the Merit scholarship from the National Science Council, Taiwan (to T.-S.T.). quantitative assays used for clinical monitoring (.50 or .75 viral mRNA copies/ml). Median viral load was 21,200 viral mRNA copies/ml (range, Address correspondence and reprint requests to I-Cheng Ho, Smith Building, Room , 526, One Jimmy Fund Way, Boston, MA 02115. E-mail address: [email protected] 75 to 233,000). Additionally, 10 HIV-uninfected healthy volunteers were included as controls. Human subject protocols were approved by all par- The online version of this article contains supplemental material. ticipating hospitals and clinics, and all subjects provided written informed Abbreviations used in this article: ChIP, chromatin immunoprecipitation; CM, cen- consent prior to enrollment. tral memory; DN, double-negative; DP, double-positive; EM, effector memory; Ets-1, E26 transformation-specific sequence; HET, Ets-1 heterozygous (Ets-1+/2 ); KO, Ets- Mice 2/2 1 ; b2m, b2-microglobulin; SP, single-positive; WT, wild-type. Ets-1–deficient mice were described previously (20). Mice were back- Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 crossed to the C57BL/6 background for six generations and maintained www.jimmunol.org/cgi/doi/10.4049/jimmunol.1002099 970 Ets-1 CONTROLS IL7-R EXPRESSION by mating Ets-1+/2 male to Ets-1+/2 female mice. Ets-1+/+ (Ets-1 wild-type Luciferase assays and chromatin immunoprecipitation assay [WT]; designated WT), Ets-1+/2 (Ets-1 heterozygous; designated HET) and Ets-12/2 (KO) littermates were used throughout the studies. Congenic Luciferase assays were performed as described (17). The CD127 promoter CD45.1 C57BL/6 and CD45.1 Rag22/2 mice were purchased from Ta- construct pGL3-IL-7Rapr, the Ets-1 p51 expression vector pcDNA-Ets-1 conic (Hudson, NY). The animals were housed under specific pathogen- p51, and the Runx1 expression vector pcDNA-MycRunx1 have been de- free conditions, and all experiments were carried out in accordance with scribed elsewhere (12, 21, 22). Chromatin immunoprecipitation (ChIP) the institutional guidelines for animal care at the Dana-Farber Cancer In- assays were performed as described using in vitro differentiated Th1 cells stitute (Boston, MA). (12). Precipitated DNA fragments were amplified by quantitative PCR. The Abs used for immunoprecipitation were anti–Ets-1 C-20 and control rabbit IgG (both Santa Cruz Biotechnology). Specific binding was calcu- Cell lysates, Western blot, and Abs 2 lated as 2 (CtEts1 / CtCtrl). The following primer pairs were used: CD127 pro- Total cell lysates and nuclear or cytosolic extracts were adjusted for total moter Ets binding site, 59-ACCACAGACAGGGAACTATG-39 and 59-CAC- protein content and subjected to SDS-PAGE followed by Western blot. The ACTCTACCTCTCCGTTT-39;IFN-g promoter, 59-CTTTCAGAGAATCC- following Abs were used: anti-STAT5 and anti–phospho-STAT5 (Tyr694) CACAAG-39 and 59-TTAAGATGGTGACAGATAGGTG-39;TLR7,59-TC- (Cell Signaling Technology, Danvers, MA) and anti-Hsp90 (Santa Cruz TAGAGTCTTTGGGTTTCG-39 and 59-TTCTGTCAAATGCTTGTCTG-39. Biotechnology, Santa Cruz, CA). As secondary Abs, HRP-coupled goat- anti–rabbit IgG was used (Zymed Laboratories). Proteins were visualized Quantitative RNA analysis using an ECL kit (PerkinElmer). RNA isolation, reverse transcription, and real-time PCR were performed as described (13). The following primer pairs were used: mouse CD127, 59- Cell isolation and culture, reagents, flow cytometry GCGGACGATCACTCCTTCTG-39 and 59-AGCCCCACATATTTGAAA- TTCCA-39; human CD127, 59-CCCTCGTGGAGGTAAAGTGC-39 and Mouse T cells were isolated from lymph nodes and spleen using magnetic 59-CCTTCCCGATAGACGACACTC-39; human/mouse Ets-1 p51, 59-CT- cell sorting as described (12). For staining of human CD127, the Alexa 9 9 647-coupled Ab from eBioscience (San Diego, CA) was used; all other CCTATGACAGCTTCGACT-3 and 5 -ATCTCCTGTCCAGCTGATAA- 9 b b 9 9 Abs used for flow cytometry were purchased from BD Biosciences 3 ; human 2-microglobulin ( 2m), 5 -GTGGCCTTAGCTGTGCTCG-3 and 59-ACCTGAATGCTGGATAGCCTC-39; human Actin, 59-GTGACAG- (Franklin Lakes, NJ). Flow cytometry was performed on a FACSCanto CAGTCGGTTGGAG-39 and 59-AGGACTGGGCCATTCTCCTT-39;mouse (murine samples) or LSRII (human samples) and analyzed with FlowJo + Actin, 59-GGCTGTATTCCCCTCCATCG-39 and 59-CCAGTTGGTAAC- software. Isolation of CD8 T cell subsets from PBMCs of HIV-positive AATGCCATG-39. and HIV-negative subjects was performed on a FACSAria (BD Bio- sciences) equipped for biohazardous material. PBMCs were stained with lineage exclusion Abs (CD4, CD14, CD19, and CD56 conjugated to V450; Statistical analysis all BD Biosciences), anti-CD27 PE (BD), anti-CD45RA allophycocyanin Statistical analysis was done using Prism Software (GraphPad, La Jolla, (BD), and CD127-PerCP Cy 5.5 (eBioscience).
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