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International Journal of Hematology
Published in: International Journal of Hematology 2/2017

01-02-2017 | Progress in Hematology

Harnessing bone marrow resident regulatory T cells to improve allogeneic stem cell transplant outcomes

Authors: Laetitia Le Texier, Katie E. Lineburg, Kelli P. A. MacDonald

Published in: International Journal of Hematology | Issue 2/2017

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Abstract

Regulatory T cells (Treg) are a suppressive T cell population which play a crucial role in the establishment of tolerance after stem cell transplantation (SCT) by controlling the effector T cell responses that drive acute and chronic GVHD. The BM compartment is enriched in a highly suppressive, activated/memory autophagy-dependent Treg population, which contributes to the HSC engraftment and the control of GVHD. G-CSF administration releases Treg from the BM through disruption of the CXCR4/SDF-1 axis and further improves Treg survival following SCT through the induction of autophagy. However, AMD3100 is more efficacious in mobilizing these Treg highlighting the potential for optimized mobilization regimes to produce more tolerogenic grafts. Notably, the disruption of adhesive interaction between integrins and their ligands contributes to HSC mobilization and may be relevant for BM Treg. Importantly, the Tregs in the BM niche contribute to maintenance of the HSC niche and appear required for optimal control of GVHD post-transplant. Although poorly studied, the BM Treg appear phenotypically and functionally unique to Treg in the periphery. Understanding the requirements for maintaining the enrichment, function and survival of BM Treg needs to be further investigated to improve therapeutic strategies and promote tolerance after SCT.
Literature
1.
Anasetti C, Logan BR, Lee SJ, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367(16):1487–96.CrossRefPubMed
2.
Bensinger WI, Weaver CH, Appelbaum FR, et al. Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony-stimulating factor. Blood. 1995;85(6):1655–8.PubMed
3.
Pavletic ZS, Joshi SS, Pirruccello SJ, et al. Lymphocyte reconstitution after allogeneic blood stem cell transplantation for hematologic malignancies. Bone Marrow Transplant. 1998;21(1):33–41.CrossRefPubMed
4.
Yang JZ, Zhang JQ, Sun LX. Mechanisms for T cell tolerance induced with granulocyte colony-stimulating factor. Mol Immunol. 2016;70:56–62.CrossRefPubMed
5.
Arpinati M, Green CL, Heimfeld S, Heuser JE, Anasetti C. Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. Blood. 2000;95(8):2484–90.PubMed
6.
Morris ES, MacDonald KP, Rowe V, et al. Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance. Blood. 2004;103(9):3573–81.CrossRefPubMed
7.
Pan L, Delmonte J Jr, Jalonen CK, Ferrara JL. Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease. Blood. 1995;86(12):4422–9.PubMed
8.
Wolf D, Wolf AM, Fong D, et al. Regulatory T-cells in the graft and the risk of acute graft-versus-host disease after allogeneic stem cell transplantation. Transplantation. 2007;83(8):1107–13.CrossRefPubMed
9.
Vasu S, Geyer S, Bingman A, et al. Granulocyte colony-stimulating factor-mobilized allografts contain activated immune cell subsets associated with risk of acute and chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2016;22(4):658–68.CrossRefPubMed
10.
Rezvani K, Mielke S, Ahmadzadeh M, et al. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood. 2006;108(4):1291–7.CrossRefPubMedPubMedCentral
11.
12.
Robb RJ, Lineburg KE, Kuns RD, et al. Identification and expansion of highly suppressive CD8(+)FoxP3(+) regulatory T cells after experimental allogeneic bone marrow transplantation. Blood. 2012;119(24):5898–908.CrossRefPubMed
13.
Zhang P, Tey SK, Koyama M, et al. Induced regulatory T cells promote tolerance when stabilized by rapamycin and IL-2 in vivo. J Immunol. 2013;191(10):5291–303.CrossRefPubMed
14.
Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9(9):1144–50.CrossRefPubMed
15.
Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JL. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood. 1997;90(8):3204–13.PubMed
16.
Hill GR, Ferrara JL. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood. 2000;95(9):2754–9.PubMed
17.
Antin JH, Ferrara JL. Cytokine dysregulation and acute graft-versus-host disease. Blood. 1992;80(12):2964–8.PubMed
18.
Sakoda Y, Hashimoto D, Asakura S, et al. Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease. Blood. 2007;109(4):1756–64.CrossRefPubMed
19.
Danby RD, Zhang W, Medd P, et al. High proportions of regulatory T cells in PBSC grafts predict improved survival after allogeneic haematopoietic SCT. Bone Marrow Transplant. 2016;51(1):110–8.CrossRefPubMed
20.
Chen X, Vodanovic-Jankovic S, Johnson B, Keller M, Komorowski R, Drobyski WR. Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease. Blood. 2007;110(10):3804–13.CrossRefPubMedPubMedCentral
21.
Zorn E, Kim HT, Lee SJ, et al. Reduced frequency of FOXP3+CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease. Blood. 2005;106(8):2903–11.CrossRefPubMedPubMedCentral
22.
Rieger K, Loddenkemper C, Maul J, et al. Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD. Blood. 2006;107(4):1717–23.CrossRefPubMed
23.
Matsuoka K, Kim HT, McDonough S, et al. Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation. J Clin Invest. 2010;120(5):1479–93.CrossRefPubMedPubMedCentral
24.
Zou L, Barnett B, Safah H, et al. Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res. 2004;64(22):8451–5.CrossRefPubMed
25.
Zhao E, Wang L, Dai J, et al. Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer. Oncoimmunology. 2012;1(2):152–61.CrossRefPubMedPubMedCentral
26.
Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6(4):345–52.CrossRefPubMed
27.
Haribhai D, Lin W, Edwards B, et al. A central role for induced regulatory T cells in tolerance induction in experimental colitis. J Immunol. 2009;182(6):3461–8.CrossRefPubMedPubMedCentral
28.
Haribhai D, Williams JB, Jia S, et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity. 2011;35(1):109–22.CrossRefPubMedPubMedCentral
29.
Joller N, Lozano E, Burkett PR, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity. 2014;40(4):569–81.CrossRefPubMedPubMedCentral
30.
Firan M, Dhillon S, Estess P, Siegelman MH. Suppressor activity and potency among regulatory T cells is discriminated by functionally active CD44. Blood. 2006;107(2):619–27.CrossRefPubMedPubMedCentral
31.
Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25(6):977–88.CrossRefPubMed
32.
Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature. 1998;393(6685):595–9.CrossRefPubMed
33.
Greenbaum AM, Link DC. Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization. Leukemia. 2011;25(2):211–7.CrossRefPubMed
34.
MacDonald KP, Le Texier L, Zhang P, et al. Modification of T cell responses by stem cell mobilization requires direct signaling of the T cell by G-CSF and IL-10. J Immunol. 2014;192(7):3180–9.CrossRefPubMedPubMedCentral
35.
Le Texier L, Lineburg KE, Cao B, et al. Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease. JCI Insight. 2016;1(15):e86850.CrossRefPubMedPubMedCentral
36.
Ukena SN, Velaga S, Goudeva L, et al. Human regulatory T cells of G-CSF mobilized allogeneic stem cell donors qualify for clinical application. PLoS One. 2012;7(12):e51644.CrossRefPubMedPubMedCentral
37.
38.
Bonig H, Chudziak D, Priestley G, Papayannopoulou T. Insights into the biology of mobilized hematopoietic stem/progenitor cells through innovative treatment schedules of the CXCR4 antagonist AMD3100. Exp Hematol. 2009;37(3):402.e401–415.e401.CrossRef
39.
Cao B, Zhang Z, Grassinger J, et al. Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist. Nat Commun. 2016;7:11007.CrossRefPubMedPubMedCentral
40.
Bonig H, Watts KL, Chang KH, Kiem HP, Papayannopoulou T. Concurrent blockade of alpha4-integrin and CXCR4 in hematopoietic stem/progenitor cell mobilization. Stem Cells. 2009;27(4):836–7.CrossRefPubMedPubMedCentral
41.
Craddock CF, Nakamoto B, Elices M, Papayannopoulou T. The role of CS1 moiety of fibronectin in VLA mediated haemopoietic progenitor trafficking. Br J Haematol. 1997;97(1):15–21.CrossRefPubMed
42.
Craddock CF, Nakamoto B, Andrews RG, Priestley GV, Papayannopoulou T. Antibodies to VLA4 integrin mobilize long-term repopulating cells and augment cytokine-induced mobilization in primates and mice. Blood. 1997;90(12):4779–88.PubMed
43.
Papayannopoulou T, Craddock C, Nakamoto B, Priestley GV, Wolf NS. The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen. Proc Natl Acad Sci USA. 1995;92(21):9647–51.CrossRefPubMedPubMedCentral
44.
Papayannopoulou T, Priestley GV, Nakamoto B. Anti-VLA4/VCAM-1-induced mobilization requires cooperative signaling through the kit/mkit ligand pathway. Blood. 1998;91(7):2231–9.PubMed
45.
Ramirez P, Rettig MP, Uy GL, et al. BIO5192, a small molecule inhibitor of VLA-4, mobilizes hematopoietic stem and progenitor cells. Blood. 2009;114(7):1340–3.CrossRefPubMedPubMedCentral
46.
Velders GA, Pruijt JF, Verzaal P, et al. Enhancement of G-CSF-induced stem cell mobilization by antibodies against the beta 2 integrins LFA-1 and Mac-1. Blood. 2002;100(1):327–33.CrossRefPubMed
47.
Stassen M, Fondel S, Bopp T, et al. Human CD25+ regulatory T cells: two subsets defined by the integrins alpha 4 beta 7 or alpha 4 beta 1 confer distinct suppressive properties upon CD4+ T helper cells. Eur J Immunol. 2004;34(5):1303–11.CrossRefPubMed
48.
Glatigny S, Duhen R, Arbelaez C, Kumari S, Bettelli E. Integrin alpha L controls the homing of regulatory T cells during CNS autoimmunity in the absence of integrin alpha 4. Sci Rep. 2015;5:7834.CrossRefPubMedPubMedCentral
49.
Siewert C, Lauer U, Cording S, et al. Experience-driven development: effector/memory-like alphaE + Foxp3+ regulatory T cells originate from both naive T cells and naturally occurring naive-like regulatory T cells. J Immunol. 2008;180(1):146–55.CrossRefPubMed
50.
Zhao D, Zhang C, Yi T, et al. In vivo-activated CD103+CD4+ regulatory T cells ameliorate ongoing chronic graft-versus-host disease. Blood. 2008;112(5):2129–38.CrossRefPubMedPubMedCentral
51.
Fischer A, Zundler S, Atreya R, et al. Differential effects of alpha4beta7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo. Gut. 2015.
52.
Ermann J, Hoffmann P, Edinger M, et al. Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood. 2005;105(5):2220–6.CrossRefPubMed
53.
Braun A, Dewert N, Brunnert F, et al. Integrin alphaE(CD103) is involved in regulatory T-cell function in allergic contact hypersensitivity. J Invest Dermatol. 2015;135(12):2982–91.CrossRefPubMed
54.
55.
Wei J, Long L, Yang K, et al. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat Immunol. 2016;17(3):277–85.CrossRefPubMedPubMedCentral
56.
Arbez J, Saas P, Lamarthee B, et al. Impact of donor hematopoietic cells mobilized with G-CSF and plerixafor on murine acute graft-versus-host-disease. Cytotherapy. 2015;17(7):948–55.CrossRefPubMed
57.
Fujisaki J, Wu J, Carlson AL, et al. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature. 2011;474(7350):216–9.CrossRefPubMedPubMedCentral
58.
Kim S, Park K, Choi J, et al. Foxp3+ regulatory T cells ensure B lymphopoiesis by inhibiting the granulopoietic activity of effector T cells in mouse bone marrow. Eur J Immunol. 2015;45(1):167–79.CrossRefPubMed
59.
Shono Y, Shiratori S, Kosugi-Kanaya M, et al. Bone marrow graft-versus-host disease: evaluation of its clinical impact on disrupted hematopoiesis after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20(4):495–500.CrossRefPubMed
60.
Shono Y, Ueha S, Wang Y, et al. Bone marrow graft-versus-host disease: early destruction of hematopoietic niche after MHC-mismatched hematopoietic stem cell transplantation. Blood. 2010;115(26):5401–11.CrossRefPubMed
61.
Luo CY, Wang L, Sun C, Li DJ. Estrogen enhances the functions of CD4(+)CD25(+)Foxp3(+) regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro. Cell Mol Immunol. 2011;8(1):50–8.CrossRefPubMed
62.
Tian T, Yu S, Liu L, et al. The profile of T helper subsets in bone marrow microenvironment is distinct for different stages of acute myeloid leukemia patients and chemotherapy partly ameliorates these variations. PLoS One. 2015;10(7):e0131761.CrossRefPubMedPubMedCentral
63.
Seddiki N, Santner-Nanan B, Martinson J, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203(7):1693–700.CrossRefPubMedPubMedCentral
64.
Liu W, Putnam AL, Xu-Yu Z, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203(7):1701–11.CrossRefPubMedPubMedCentral
65.
Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol. 2004;4(9):665–74.CrossRefPubMed
66.
Malek TR, Yu A, Vincek V, Scibelli P, Kong L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity. 2002;17(2):167–78.CrossRefPubMed
67.
Levings MK, Sangregorio R, Roncarolo MG. Human cd25(+)cd4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med. 2001;193(11):1295–302.CrossRefPubMedPubMedCentral
68.
Thornton AM, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 2000;164(1):183–90.CrossRefPubMed
69.
70.
Simonetta F, Chiali A, Cordier C, et al. Increased CD127 expression on activated FOXP3+CD4+ regulatory T cells. Eur J Immunol. 2010;40(9):2528–38.CrossRefPubMed
71.
Mazzucchelli R, Hixon JA, Spolski R, et al. Development of regulatory T cells requires IL-7Ralpha stimulation by IL-7 or TSLP. Blood. 2008;112(8):3283–92.CrossRefPubMedPubMedCentral
72.
Simonetta F, Gestermann N, Martinet KZ, et al. Interleukin-7 influences FOXP3+CD4+ regulatory T cells peripheral homeostasis. PLoS One. 2012;7(5):e36596.CrossRefPubMedPubMedCentral
73.
Schmaler M, Broggi MA, Lagarde N, et al. IL-7R signaling in regulatory T cells maintains peripheral and allograft tolerance in mice. Proc Natl Acad Sci USA. 2015;112(43):13330–5.CrossRefPubMedPubMedCentral
74.
Goldrath AW, Sivakumar PV, Glaccum M, et al. Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory CD8+ T cells. J Exp Med. 2002;195(12):1515–22.CrossRefPubMedPubMedCentral
75.
Schluns KS, Williams K, Ma A, Zheng XX, Lefrancois L. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol. 2002;168(10):4827–31.CrossRefPubMed
76.
Becker TC, Coley SM, Wherry EJ, Ahmed R. Bone marrow is a preferred site for homeostatic proliferation of memory CD8 T cells. J Immunol. 2005;174(3):1269–73.CrossRefPubMed
77.
Mazo IB, Honczarenko M, Leung H, et al. Bone marrow is a major reservoir and site of recruitment for central memory CD8+ T cells. Immunity. 2005;22(2):259–70.CrossRefPubMed
78.
Yang N, Baban B, Isales CM, Shi XM. Crosstalk between bone marrow-derived mesenchymal stem cells and regulatory T cells through a glucocorticoid-induced leucine zipper/developmental endothelial locus-1-dependent mechanism. FASEB J. 2015;29(9):3954–63.CrossRefPubMedPubMedCentral
79.
Ayroldi E, Migliorati G, Bruscoli S, et al. Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor kappaB. Blood. 2001;98(3):743–53.CrossRefPubMed
80.
Koreth J, Kim HT, Jones KT, et al. Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease. Blood. 2016;128(1):130–7.CrossRefPubMed
81.
Matsuoka K, Koreth J, Kim HT, et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med. 2013;5(179):179ra143.CrossRef
Metadata
Title
Harnessing bone marrow resident regulatory T cells to improve allogeneic stem cell transplant outcomes
Authors
Laetitia Le Texier
Katie E. Lineburg
Kelli P. A. MacDonald
Publication date
01-02-2017
Publisher
Springer Japan
Published in
International Journal of Hematology / Issue 2/2017
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-016-2161-5

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