Role for granulocyte colony–stimulating factor in the generation of human T regulatory type 1 cells
Tóm tắt
Granulocyte colony–stimulating factor (G-CSF) may affect T-cell homeostasis by multiple mechanisms, inducing polarization of cytokine secretion, inhibition of T-cell proliferation, and enhancement of T-cell apoptosis. We analyzed the production of interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1) by T cells from healthy volunteer donors treated with recombinant human G-CSF. Highly purified CD4+ T cells obtained before and after G-CSF administration (pre-G and post-G, respectively) were activated using the allogeneic mixed leukocyte reaction. Post-G CD4+T cells produced high levels of IL-10 but undetectable levels of IL-2 and IL-4, whereas the level of TGF-β1 release was comparable to that of pre-G CD4+ T cells. Notably, post-G CD4+ T cells proliferated poorly in response to alloantigens and to recall antigens and suppressed the proliferation of autologous CD4+ T cells in a cell contact–independent and an antigen-nonspecific manner. TGF-β1 and IL-10 were not dispensable for post-G CD4+ T cells to mediate suppression, as shown by neutralization studies. Compared with pre-G CD4+ T cells, alloantigen-activated post-G CD4+ T cells preferentially expressed markers associated with memory T cells, in conjunction with reduced levels of CD28 and CD62L. Collectively, these data demonstrate that CD4+ T cells exposed to G-CSF in vivo acquire the properties of T regulatory (Tr) cells once triggered in vitro through the T-cell receptor, including a peculiar cytokine production profile (IL-10++TGF-β1+IL-2low/−IL-4low/−), an intrinsic low proliferative capacity, and a contact-independent suppression of antigen-driven proliferation. Tr cells generated ex vivo after exposure to G-CSF might be clinically relevant for transplantation medicine and for the treatment of human immune-mediated diseases.
Tài liệu tham khảo
Champlin, 2000, Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation., Blood., 95, 3702
Weissman, 2000, Translating stem and progenitor cell biology to the clinic: barriers and opportunities., Science., 287, 1442, 10.1126/science.287.5457.1442
Rutella, 1999, Recombinant human granulocyte colony-stimulating factor (rhG-CSF): effects on lymphocyte phenotype and function., J Interferon Cytokine Res., 19, 989, 10.1089/107999099313181
Mielcarek, 1998, Production of interleukin-10 by granulocyte colony-stimulating factor–mobilized blood products: a mechanism for monocyte-mediated suppression of T-cell proliferation., Blood., 92, 215, 10.1182/blood.V92.1.215.413k10_215_222
Boneberg, 2000, Human monocytes express functional receptors for granulocyte colony-stimulating factor that mediate suppression of monokines and interferon-γ., Blood., 95, 270, 10.1182/blood.V95.1.270
Sloand, 2000, Pharmacologic doses of granulocyte colony-stimulating factor affect cytokine production by lymphocytes in vitro and in vivo., Blood., 95, 2269, 10.1182/blood.V95.7.2269
Tayebi, 2001, Effect of granulocyte colony-stimulating factor mobilization on phenotypical and functional properties of immune cells., Exp Hematol., 29, 458, 10.1016/S0301-472X(01)00613-0
Nawa, 2000, G-CSF reduces IFN-γ and IL-4 production by T cells after allogeneic stimulation by indirectly modulating monocyte function., Bone Marrow Transplant., 25, 1035, 10.1038/sj.bmt.1702402
Rutella, 1998, Serum of healthy donors receiving recombinant human granulocyte colony-stimulating factor (rhG-CSF) induces T-cell unresponsiveness., Exp Hematol., 26, 1024
Rutella, 2000, Granulocyte colony-stimulating factor perturbs lymphocyte mitochondrial function and inhibits cell cycle progression., Exp Hematol., 28, 612, 10.1016/S0301-472X(00)00164-8
Rutella, 2001, T-cell apoptosis induced by granulocyte colony-stimulating factor (G-CSF) is associated with retinoblastoma protein phosphorylation and reduced expression of cyclin-dependent kinase inhibitors., Exp Hematol., 29, 401, 10.1016/S0301-472X(01)00617-8
Roncarolo, 2000, The role of different subsets of T regulatory cells in controlling autoimmunity., Curr Opin Immunol., 12, 676, 10.1016/S0952-7915(00)00162-X
Groux, 1997, A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis., Nature., 389, 737, 10.1038/39614
Wu, 2001, Tolerance to cyclosporin A-induced autologous graft-versus-host disease is mediated by a CD4+CD25+ subset of recent thymic emigrants., J Immunol., 166, 7158, 10.4049/jimmunol.166.12.7158
Letterio, 1998, Regulation of immune responses by TGF-β., Annu Rev Immunol., 16, 137, 10.1146/annurev.immunol.16.1.137
Prud'homme, 2000, The inhibitory effects of transforming growth factor-beta-1 (TGF-β1) in autoimmune diseases., J Autoimmun., 14, 23, 10.1006/jaut.1999.0339
Joss, 2000, IL-10 directly acts on T cells by specifically altering the CD28 co-stimulation pathway., Eur J Immunol., 30, 1683, 10.1002/1521-4141(200006)30:6<1683::AID-IMMU1683>3.0.CO;2-A
D'Orazio, 1998, A novel role for TGF-β and IL-10 in the induction of immune privilege., J Immunol., 160, 2089, 10.4049/jimmunol.160.5.2089
Zeller, 1999, Induction of CD4+ T cell alloantigen-specific hyporesponsiveness by IL-10 and TGF-β., J Immunol., 163, 3684, 10.4049/jimmunol.163.7.3684
Boussiotis, 2001, Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-β-treated alloreactive T cells that do not induce graft-versus-host disease., Blood., 97, 565, 10.1182/blood.V97.2.565
Maino, 1998, Identification of functional subsets by flow cytometry: intracellular detection of cytokine expression., Cytometry., 34, 207, 10.1002/(SICI)1097-0320(19981015)34:5<207::AID-CYTO1>3.0.CO;2-J
Testa, 1994, Autologous stem cell transplantation: release of early- and late-acting growth factors relates with hematopoietic ablation and recovery., Blood., 84, 3532, 10.1182/blood.V84.10.3532.3532
Rutella, 2001, Immune reconstitution after autologous peripheral blood progenitor cell transplantation: effect of interleukin-15 on T-cell survival and effector functions., Exp Hematol., 29, 1503, 10.1016/S0301-472X(01)00747-0
Pierelli, 2000, Modulation of Bcl-2 RNA/protein and p27 protein in human primitive hematopoietic progenitors by autocrine TGF-β is a cell cycle independent effect and influences their hematopoietic potential., Blood., 95, 3001, 10.1182/blood.V95.10.3001
De Candia, 2001, Binding of α-thrombin to glycoprotein Ibα accelerates the hydrolysis of PAR-1 on intact platelets., J Biol Chem., 276, 4692, 10.1074/jbc.M008160200
Sakaguchi, 2000, Regulatory T cells: key controllers of immunologic self-tolerance., Cell., 101, 455, 10.1016/S0092-8674(00)80856-9
Volpi, 2001, Postgrafting administration of granulocyte colony-stimulating factor impairs functional immune recovery in recipients of human leukocyte antigen haplotype-mismatched hematopoietic transplants., Blood., 97, 2514, 10.1182/blood.V97.8.2514
Baecher-Allan, 2001, CD4+CD25high regulatory cells in human peripheral blood., J Immunol., 167, 1245, 10.4049/jimmunol.167.3.1245
Jonuleit, 2001, Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood., J Exp Med., 193, 1285, 10.1084/jem.193.11.1285
Nakamura, 2001, Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor-β., J Exp Med., 194, 629, 10.1084/jem.194.5.629
Yamagiwa, 2001, A role for TGF-β in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood., J Immunol., 166, 7282, 10.4049/jimmunol.166.12.7282
Dieckmann, 2001, Ex vivo isolation and characterization of CD4+CD25+ T cells with regulatory properties from human blood., J Exp Med., 193, 1303, 10.1084/jem.193.11.1303
Thornton, 1998, CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production., J Exp Med., 188, 287, 10.1084/jem.188.2.287
Maloy, 2001, Regulatory T cells in the control of immune pathology., Nat Immunol., 2, 816, 10.1038/ni0901-816
Shevach, 2001, Certified professionals: CD4+CD25+ suppressor T cells., J Exp Med., 193, F41, 10.1084/jem.193.11.F41
Waldmann, 2001, Regulating the immune response to transplants: a role for CD4+ regulatory cells?, Immunity., 14, 399, 10.1016/S1074-7613(01)00120-0
Annacker, 2001, CD25+CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10., J Immunol., 166, 3008, 10.4049/jimmunol.166.5.3008
Asseman, 1999, An essential role for interleukin-10 in the function of regulatory T cells that inhibit intestinal inflammation., J Exp Med., 190, 995, 10.1084/jem.190.7.995
Suchin, 2001, Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question., J Immunol., 166, 973, 10.4049/jimmunol.166.2.973
Hendriks, 1999, Expression of the transcription factor GATA-3 is required for the development of the earliest T cell progenitors and correlates with stages of cellular proliferation in the thymus., Eur J Immunol., 29, 1912, 10.1002/(SICI)1521-4141(199906)29:06<1912::AID-IMMU1912>3.0.CO;2-D
Pan, 1995, 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., 86, 4422, 10.1182/blood.V86.12.4422.bloodjournal86124422
Sugimori, 1999, Administration of G-CSF to normal individuals diminishes L-selectin+ T cells in the peripheral blood that respond better to alloantigen stimulation than L-selectin− T cells., Bone Marrow Transplant., 23, 119, 10.1038/sj.bmt.1701552
Tanaka, 1998, Impaired induction of the CD28-responsive complex in granulocyte colony-stimulating factor mobilized CD4 T cells., Blood., 91, 347, 10.1182/blood.V91.1.347
Moser, 2001, Lymphocyte traffic control by chemokines., Nat Immunol., 2, 123, 10.1038/84219
Rutella, 2000, Homogeneous expression of CXC chemokine receptor 4 (CXCR4) on G-CSF–mobilized peripheral blood CD34+ cells [letter]., Blood., 95, 4015, 10.1182/blood.V95.12.4015
Iellem, 2001, Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4+CD25+ regulatory T cells., J Exp Med., 194, 847, 10.1084/jem.194.6.847
Sallusto, 1999, Two subsets of memory T lymphocytes with distinct homing potentials and effector functions., Nature., 401, 708, 10.1038/44385
Murdoch, 2000, Chemokine receptors and their role in inflammation and infectious diseases., Blood., 95, 3032, 10.1182/blood.V95.10.3032
Levings, 2001, 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., 193, 1295, 10.1084/jem.193.11.1295
Barrat, 2002, In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper 1 (Th1)- and Th2-inducing cytokines., J Exp Med., 195, 603, 10.1084/jem.20011629
Gregori, 2001, Regulatory T cells induced by 1α,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance., J Immunol., 167, 1945, 10.4049/jimmunol.167.4.1945
Sanchez-Fueyo, 2002, Tracking the immunoregulatory mechanisms active during allograft tolerance., J Immunol., 168, 2274, 10.4049/jimmunol.168.5.2274
Bacchetta, 1994, High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells., J Exp Med., 179, 493, 10.1084/jem.179.2.493
Levings, 2001, IFN-α and IL-10 induce the differentiation of human type 1 T regulatory cells., J Immunol., 166, 5530, 10.4049/jimmunol.166.9.5530
Seo, 2001, Interleukin-10 expressed at early tumor sites induces subsequent generation of CD4+ T-regulatory cells and systemic collapse of antitumor immunity., Immunology., 103, 449, 10.1046/j.1365-2567.2001.01279.x
Woo, 2001, Regulatory CD4+CD25+ T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer., Cancer Res., 61, 4766