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Of the T Cell by G-CSF and IL-10 Cell Mobilization Requires Direct Downloaded from http://www.jimmunol.org/ by guest on September 26, 2021 is online at: average * The Journal of Immunology , 26 of which you can access for free at: 2014; 192:3180-3189; Prepublished online 28 from submission to initial decision 4 weeks from acceptance to publication February 2014; doi: 10.4049/jimmunol.1302315 http://www.jimmunol.org/content/192/7/3180 Modification of T Cell Responses by Stem Cell Mobilization Requires Direct Signaling of the T Cell by G-CSF and IL-10 Kelli P. A. MacDonald, Laetitia Le Texier, Ping Zhang, Helen Morris, Rachel D. Kuns, Katie E. Lineburg, Lucie Leveque, Alistair L. Don, Kate A. Markey, Slavica Vuckovic, Frederik O. Bagger, Glen M. Boyle, Bruce R. Blazar and Geoffrey R. Hill J Immunol cites 45 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription http://www.jimmunol.org/content/suppl/2014/02/28/jimmunol.130231 5.DCSupplemental This article http://www.jimmunol.org/content/192/7/3180.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology 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. This information is current as of September 26, 2021. The Journal of Immunology Modification of T Cell Responses by Stem Cell Mobilization Requires Direct Signaling of the T Cell by G-CSF and IL-10 Kelli P. A. MacDonald,* Laetitia Le Texier,* Ping Zhang,* Helen Morris,* Rachel D. Kuns,* Katie E. Lineburg,* Lucie Leveque,* Alistair L. Don,* Kate A. Markey,* Slavica Vuckovic,* Frederik O. Bagger,† Glen M. Boyle,* Bruce R. Blazar,‡ and Geoffrey R. Hill*,x The majority of allogeneic stem cell transplants are currently undertaken using G-CSF mobilized peripheral blood stem cells. G-CSF has diverse biological effects on a broad range of cells and IL-10 is a key regulator of many of these effects. Using mixed radiation chimeras in which the hematopoietic or nonhematopoietic compartments were wild-type, IL-102/2, G-CSFR2/2,or combinations thereof we demonstrated that the attenuation of alloreactive T cell responses after G-CSF mobilization required Downloaded from direct signaling of the T cell by both G-CSF and IL-10. IL-10 was generated principally by radio-resistant tissue, and was not required to be produced by T cells. G-CSF mobilization significantly modulated the transcription profile of CD4+CD25+ regula- tory T cells, promoted their expansion in the donor and recipient and their depletion significantly increased graft-versus-host disease (GVHD). In contrast, stem cell mobilization with the CXCR4 antagonist AMD3100 did not alter the donor T cell’s ability to induce acute GVHD. These studies provide an explanation for the effects of G-CSF on T cell function and demonstrate that IL- 10 is required to license regulatory function but T cell production of IL-10 is not itself required for the attenuation GVHD. http://www.jimmunol.org/ Although administration of CXCR4 antagonists is an efficient means of stem cell mobilization, this fails to evoke the immuno- modulatory effects seen during G-CSF mobilization. These data provide a compelling rationale for considering the immunological benefits of G-CSF in selecting mobilization protocols for allogeneic stem cell transplantation. The Journal of Immunology, 2014, 192: 3180–3189. raft-versus-host disease (GVHD) remains a major com- (1, 2). T cells from donors treated with G-CSF have a reduced plication following allogeneic hematopoietic stem cell capacity to induce GVHD on a per cell basis relative to those from transplantation, with the resultant multiorgan damage control-treated donors (3). The mechanism by which G-CSF pre- G by guest on September 26, 2021 and immune deficiency significantly impairing overall transplant vents GVHD has been suggested to be the result of Th2 and reg- survival. The use of recombinant human G-CSF–mobilized stem ulatory T cells (Treg) differentiation of naive donor T cells (3, 4). cell grafts has lead to rapid immune and hematopoietic reconsti- There is additional data suggesting G-CSF may also reduce GVHD tution, and superior short term and long term disease free survival through effects on dendritic cells, monocytes and NK cells (reviewed in Ref. 4). Indeed, the attenuation of T cell function by G-CSF is *QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Aus- generally thought to be an indirect effect via effects on these in- tralia; †Department of Biology, Finsen Laboratory, Rigshospitalet, Faculty of Health nate cells. Sciences, Biotech Research and Innovation Centre, University of Copenhagen, We have previously demonstrated that pegylated G-CSF is su- Copenhagen, DK-2200 Denmark; ‡Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minne- perior to standard G-CSF for the prevention of GVHD, due to apolis, MN 55455; and xDepartment of Bone Marrow Transplantation, Royal Bris- the enhanced generation of IL-10–producing Treg (5). Indeed, bane Hospital, Brisbane, Queensland 4006, Australia the induction of Th2 cells and Tregs by G-CSF are well de- Received for publication September 5, 2013. Accepted for publication January 30, scribed and dependent on the dose and type of G-CSF molecule 2014. used (3, 4, 6). In these studies, we investigated the greater unan- This work was supported by grants from the National Health and Medical Research Council and Cancer Council Queensland. K.P.A.M. is a Cancer Council Queensland swered question surrounding how T cell function is modified by Senior Research Fellow. G.R.H. is a National Health and Medical Research Council G-CSF and whether these effects are recapitulated by mobilization Australian Fellow and Queensland Health Senior Clinical Research Fellow. K.A.M. with CXCR4 antagonists, which are also used for stem cell mo- is a National Health and Medical Research Council Clinical Training Fellow. bilization. K.P.A.M. designed and performed experiments, analyzed data, and wrote the manu- script; L.L.T., P.Z., H.M., L.L., and S.V. performed experiments; R.D.K., K.E.L., K.A.M., and A.L.D. assisted with experimental work, animal breeding, and moni- Materials and Methods toring; F.O.B. and G.M.B. assisted with microarray analysis; B.R.B. provided critical review of data and manuscript; and G.R.H. assisted with experimental design, data Mice analysis, and manuscript preparation. Female C57BL/6 (B6.WT, H-2b, CD45.2+), B6.Ptprca (H-2b, CD45.1+), b/d + Address correspondence and reprint requests to Dr. Kelli P. A. MacDonald, QIMR and B6D2F1 (H-2 , CD45.2 ) mice were purchased from the Animal Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Aus- Resources Centre (Perth, WA, Australia). B6.IL-102/2 (H-2b) and B6.G- tralia. E-mail address: [email protected] CSFR2/2 (H-2b) were supplied from the Australian National University The online version of this article contains supplemental material. and D. Link (Washington University, St. Louis, MO), respectively. Abbreviations used in this article: B6, C57BL/6; BM, bone marrow; DC, dendritic B6.Foxp3-eGFP, B6.Foxp3-GFP-Luciferase-DTR (B6.Foxp3-luci), and CD402/2 mice were supplied by the QIMR Berghofer Medical Research cell; GVHD, graft-versus-host disease; nTreg, natural regulatory T cell; Treg, regula- tory T cell. Institute animal facility. The mice were used between 8 and 12 wk of age. Mice were housed in sterilized microisolator cages and received acidified Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 autoclaved water (pH 2.5) after transplantation. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302315 The Journal of Immunology 3181 Stem cell mobilization irradiated (1000 cGy) B6.WT or B6.IL-102/2 recipients, which were then allowed to reconstitute over 4 mo before use as allograft recipients. Recombinant human pegylated-G-CSF (Amgen, Thousand Oaks, CA) was In some experiments, a combination of both B6.WT and B6.IL-102/2 or diluted with normal saline (Baxter, Deerfield, IL) and given as a single dose B6.WT and B6.G-CSFR2/2 BM cells were transplanted in 1:1 or 4:1 ratios 2 6 s.c. at 12 mg/animal on day 6 prior to transplant (5). AMD3100 (Sigma- (5 3 10 cell total) as described in figures. The degree of systemic GVHD Aldrich, St. Louis, MO) was diluted with PBS and given s.c. at 200 mg/ was assessed by scoring as previously described (maximum index = 10) 2 animal per dose (7). Donor mice received AMD3100 or saline on days 4, (11). 23, 22, and 21at24-hintervals,andspleenswereharvested1hafter the last injection. All donor spleens were harvested on day 0. Where Cell preparation indicated, natural Treg (nTreg) were depleted in vivo by i.p. administration of anti-CD25 mAb (PC61) during G-CSF mobilization at days 23 and 21 T cells were purified using magnetic bead depletion of non-T cell pretransplant. splenocytes. Briefly, following red cell lysis, splenocytes were incu- bated with purified mAb (CD19, B220, Gr-1, CD11b, and Ter119). After Stem cell transplantation incubation with Abs, cells were incubated with goat anti-rat IgG BioMag beads (Qiagen Pty, Chadstone Centre, VIC, Australia) for 20 Mice were transplanted as described previously (5, 8, 9).
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