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Cells Δγ Lineage Choice and Shapes Peripheral Purinergic P2X7

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Cells Δγ Lineage Choice and Shapes Peripheral Purinergic P2X7 Purinergic P2X7 Receptor Drives T Cell Lineage Choice and Shapes Peripheral δγ Cells This information is current as Michela Frascoli, Jessica Marcandalli, Ursula Schenk and of October 2, 2021. Fabio Grassi J Immunol 2012; 189:174-180; Prepublished online 30 May 2012; doi: 10.4049/jimmunol.1101582 http://www.jimmunol.org/content/189/1/174 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2012/05/30/jimmunol.110158 Material 2.DC1 http://www.jimmunol.org/ References This article cites 31 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/189/1/174.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 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 © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Purinergic P2X7 Receptor Drives T Cell Lineage Choice and Shapes Peripheral gd Cells Michela Frascoli,* Jessica Marcandalli,* Ursula Schenk,*,1 and Fabio Grassi*,† TCR signal strength instructs ab versus gd lineage decision in immature T cells. Increased signal strength of gdTCR with respect to pre-TCR results in induction of the gd differentiation program. Extracellular ATP evokes physiological responses through purinergic P2 receptors expressed in the plasma membrane of virtually all cell types. In peripheral T cells, ATP released upon TCR stimulation enhances MAPK activation through P2X receptors. We investigated whether extracellular ATP and P2X receptors signaling tuned TCR signaling at the ab/gd lineage bifurcation checkpoint. We show that P2X7 expression was selectively increased in immature gd+CD25+ cells. These cells were much more competent to release ATP than pre–TCR- expressing cells following TCR stimulation and Ca2+ influx. Genetic ablation as well as pharmacological antagonism of P2X7 resulted in impaired ERK phosphorylation, reduction of early growth response (Egr) transcripts induction, and diversion of gdTCR-expressing thymocytes toward the ab lineage fate. The impairment of the ERK-Egr-inhibitor of differentiation 3 (Id3) Downloaded from signaling pathway in gd cells from p2rx72/2 mice resulted in increased representation of the Id3-independent NK1.1-expressing gd T cell subset in the periphery. Our results indicate that ATP release and P2X7 signaling upon gdTCR expression in immature thymocytes constitutes an important costimulus in T cell lineage choice through the ERK-Egr-Id3 signaling pathway and con- tributes to shaping the peripheral gd T cell compartment. The Journal of Immunology, 2012, 189: 174–180. roductive rearrangement of gene segments at Tcrb, Tcrg, CD44+25+ (DN2) . CD44225+ (DN3) . CD442252 (DN4) (5). http://www.jimmunol.org/ and Tcrd loci is instrumental in T cell development in the In particular, the DN3 stage is a fundamental checkpoint at which P thymus. The protein products of these stochastic recom- pre-TCR and gd TCR signals instruct commitment to ab and gd bination events, the pre-TCR (constituted by the rearranged TCRb- lineage, respectively (6). b-Selection is associated with higher chain in covalent association with the invariant pre–TCRa-chain) CD5 and CD27 expression and increase in cell size, which define (1) and gdTCR, influence the thymocyte to commit to the ab and the DN3b stage (7, 8). Two elegant studies have shown that TCR gd lineage, respectively (2). Whereas differentiation of gd T cells signal strength rather than TCR signal quality determines lineage is generally characterized by lack of expression of CD4 and CD8 choice, a strong TCR signal resulting in gd and a weak signal in coreceptor molecules (3, 4), development of ab T cells is char- ab commitment. In fact, attenuation of gdTCR signal strength by guest on October 2, 2021 acterized by the transition of thymocytes through an ordered se- or expression level induced differentiation of gdTCR-expressing quence of phenotypes defined by the expression of CD4 and CD8. thymocytes along the ab pathway to the DP stage (9, 10). Cells progress from the most immature CD4282 double-negative Whether concomitant costimuli contribute to TCR signal strength (DN) stage to the mature either CD4+82 or CD428+ single positive in gd lineage choice is at present unknown. In addition, differential (SP) stage through an intermediate CD4+8+ double-positive (DP) signaling by the gdTCR can result in development of gd NKT cells, stage. The DN stage can be further subdivided according to the which express NK.1.1 and, in contrast with conventional gd cells, expression of CD25 and CD44 with maturation characterized are relatively independent from the ERK-early growth response phenotypically by the following sequence: CD44+252 (DN1) . (Egr)-inhibitor of differentiation 3 (Id3) signaling axis. We have previously shown that signal transduction by the TCR in peripheral CD4 T cells determines the increase in ATP synthe- *Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland; and †Dipartimento di Biologia e Genetica per le Scienze Mediche, Universita` degli Studi sis and the release through calcium-sensitive pannexin-1 hemi- di Milano, I-20133 Milano, Italy channels, which in turn activates in an autocrine fashion purinergic 1Current address: Pharmanalytica SA, Locarno, Switzerland. P2X receptors (ATP-gated nonselective cationic channels) in the Received for publication June 2, 2011. Accepted for publication April 28, 2012. plasma membrane. This signaling loop acts as a costimulus for This work was supported by Grant 310030-124745 from the Swiss National Science MAPK signaling and implements cell cycling as well as IL-2 Foundation, Grant KFS 02445-08-2009 from the Swiss Cancer League, the Fonda- secretion (11, 12). Pioneering experiments have shown that im- zione Ticinese per la Ricerca sul Cancro, the Fondazione Leonardo, the AGD Italia mature thymocytes are responsive to extracellular ATP through (Coordinamento Associazioni Italiane Giovani con Diabete), Leo Club Italia, and the Sixth Research Framework Program of the European Union, Project MUGEN P2X receptors (13). Rearrangement competent but not incompe- (MUGEN LSHG-CT-2005-005203) (to F.G.). tent DN3 thymocytes undergo spontaneous cytosolic Ca2+ oscil- Address correspondence and reprint requests to Dr. Fabio Grassi, Institute for Re- lations, which might lead to ATP release. We tested whether ATP search in Biomedicine, Via Vincenzo Vela 6, CH-6500 Bellinzona, Switzerland. released as a result of pre-TCR and/or gdTCR expression affected E-mail address: [email protected] thymocyte differentiation through P2X receptors signaling. We The online version of this article contains supplemental material. show that P2X7 receptor activation contributes to gdTCR signal Abbreviations used in this article: BzATP, benzoyl-ATP; DN, double-negative; DP, double-positive; Egr, early growth response; ERK, extracellular signal regulated strength and that genetic ablation as well as pharmacological kinase; FTOC, fetal thymic organ culture; Id3, inhibitor of differentiation 3; oATP, antagonism of P2X7 diverts gdTCR-expressing cells toward the periodate-oxidized ATP; OP9-DL1, OP9 BM stromal cell transduced with the Notch ab fate. Moreover, impaired gdTCR signaling in p2rx72/2 mice ligand Delta-like 1; SP, single-positive; WT, wild-type. resulted in increased representation of Id3-independent NK1.1+ + Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 TCR Vd6.3 cells in the periphery. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1101582 The Journal of Immunology 175 Materials and Methods ATP release was measured by means of a two-enzyme assay, as de- Mice scribed previously (16). Briefly, cells were plated on poly-L-lysine– coated coverslips, which were fixed in the recording chamber of an in- C57BL/6 (wild-type [WT]) mice were obtained from Charles River Lab- verted microscope. Cells were incubated in modified Krebs–Ringer solu- oratories Germany and p2rx72/2 (14), and rag12/2 C57BL/6 mice were tion supplemented with 8 U/ml each of hexokinase and glucose 6- obtained from The Jackson Laboratory. Mice were used at 4 wk to isolate phosphate dehydrogenase and 5 mM NADP. In the presence of ATP, these thymocytes and at 8 wk to analyze gd cells in peripheral tissues. The enzymes catalyze the formation of NADPH, a fluorescent molecule that animals were bred and treated in accordance with the Swiss Federal Vet- was visualized using fluorescence microscopy with an excitation wave- erinary Office guidelines and were kept in specific pathogen-free animal length of 340 nm and an emission at 460 nm. The fluorescence intensity of facility. regions on or outside the cells was measured using TILLvisION software, and ATP concentrations were estimated using ATP standard solutions of Flow cytometry and cell culture known concentrations. For measurement of cellular ATP, cells were lysed in 1% Triton X-100 For FACS analysis, mAbs conjugated with biotin, FITC, PE, PerCP, PerCP- and frozen on dry ice until analyzed with the ATP determination kit Cy5.5, PE-Cy7, allophycocyanin, or allophycocyanin-Cy7 against the fol- (Molecular Probes). lowing Ags were used: CD8a (53-6.7), CD4 (L3T4), CD25 (PC61.5), CD44 (IM7), CD27 (LG.7F9), CD3ε (145-2C11), TCRb (H57-597), TCRg/d Fetal thymus organ culture (GL3) (eBioscience); TCR Vg2 (UC3-10A6), TCR Vd6.3/2 (8F4H7B7) (BD Biosciences); and TCRVg3 (536) and TCR Vd4 (552143) (Bio- The medium for fetal thymus organ culture (FTOC) was IMDM plus GlutaMAX medium with 20% (v/v) FBS, 50 mM 2-ME, 1 mM sodium Legend).
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