Immune regulatory activity of CD34 (cid:1) progenitor cells: evidence for a deletion-based mechanism mediated by TNF- (cid:2)

Previous studies suggest that cells within the CD34 (cid:1) hematopoietic stem cell com-partment are endowed with immune regulatory activity. Furthermore, it is possible to expand the human regulatory cells upon short-term culture of purified CD34 (cid:1) cells with an early-acting cytokine cocktail. We now show that addition of anti-CD28, anti-CD2, interleukin-2 (IL-2), anti–IL-10, or IL-12 tothebulkmixedlymphocytereaction(MLR) cannot reverse the inhibitory activity of the CD34 (cid:1) cells,rulingoutanergy-basedmecha-nisms or mechanisms involving Th1-Th2 skewing. Furthermore, phenotyping of cells present after addition of CD34 (cid:1) cells to the bulk MLR ruled out potential induction of plasmacytoid dendritic precursors, known to be endowed with regulatory activity. In contrast, the inhibitory activity of CD34 (cid:1) cells could be reversed by adding the caspase inhibitor BD-FMK to the bulk MLR, indicatingadeletion-basedmechanism.The deletion can be inhibited by anti–tumor ne-crosisfactor- (cid:2) (anti–TNF- (cid:2) )andnotbyanti– transforming growth factor- (cid:3) (anti–TGF- (cid:3) ), suggesting a potential role for TNF- (cid:2) in the regulatory activity of CD34 (cid:1) cells. (Blood. 2005;105:2585-2593)

[1]  Sang Gyun Kim,et al.  Transforming Growth Factor-β1 Induces Apoptosis through Fas Ligand-independent Activation of the Fas Death Pathway in Human Gastric SNU-620 Carcinoma Cells , 2003 .

[2]  A. Berrebi,et al.  Tolerance induction by megadose hematopoietic progenitor cells: expansion of veto cells by short-term culture of purified human CD34(+) cells. , 2002, Blood.

[3]  B. Blazar,et al.  The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. , 2002, Blood.

[4]  C. Borror.  An Introduction to Statistical Methods and Data Analysis, 5th Ed. , 2002 .

[5]  Katia Perruccio,et al.  Effectiveness of Donor Natural Killer Cell Alloreactivity in Mismatched Hematopoietic Transplants , 2002, Science.

[6]  M. Roncarolo,et al.  Human Cd25+Cd4+ T Regulatory Cells Suppress Naive and Memory T Cell Proliferation and Can Be Expanded in Vitro without Loss of Function , 2001, The Journal of experimental medicine.

[7]  S. Reich-Zeliger,et al.  Bone marrow transplantation across major genetic barriers: the role of megadose stem cells and nonalloreactive donor anti-third party CTLS. , 2001, Transplantation proceedings.

[8]  H. Waldmann,et al.  Regulating the immune response to transplants. a role for CD4+ regulatory cells? , 2001, Immunity.

[9]  J. Kirklin,et al.  A DIFFERENTIAL REQUIREMENT FOR CD8+ DONOR CELLS IN THE AUGMENTATION OF ALLOGRAFT SURVIVAL BY POSTTRANSPLANTATION ADMINISTRATION OF DONOR SPLEEN CELLS AND DONOR BONE MARROW CELLS1 , 2000, Transplantation.

[10]  S. Reich-Zeliger,et al.  Anti-third party CD8+ CTLs as potent veto cells: coexpression of CD8 and FasL is a prerequisite. , 2000, Immunity.

[11]  J. Banchereau,et al.  Flt3-Ligand and Granulocyte Colony-Stimulating Factor Mobilize Distinct Human Dendritic Cell Subsets In Vivo1 , 2000, The Journal of Immunology.

[12]  H. Hall,et al.  CD4+CD25+ regulatory T cells down‐regulate co‐stimulatory molecules on antigen‐presenting cells , 2000, European journal of immunology.

[13]  S. Heimfeld,et al.  Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. , 2000, Blood.

[14]  M. Sykes,et al.  Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment , 2000, Nature Medicine.

[15]  M. Martelli,et al.  Transplantation tolerance induced by "mega dose" CD34+ cell transplants. , 2000, Experimental hematology.

[16]  H. Waldmann,et al.  CD40 ligand blockade induces CD4+ T cell tolerance and linked suppression. , 1999, Journal of immunology.

[17]  G. Stingl,et al.  Survival, maturation, and function of CD11c- and CD11c+ peripheral blood dendritic cells are differentially regulated by cytokines. , 1999, Journal of immunology.

[18]  R. Lechler,et al.  Critical role of costimulation in the activation of naive antigen-specific TCR transgenic CD8+ T cells in vitro. , 1999, Journal of immunology.

[19]  M. Martelli,et al.  Stem cell escalation enables HLA-disparate haematopoietic transplants in leukaemia patients. , 1999, Immunology today.

[20]  R. Rich,et al.  Antiretroviral Cytolytic T-Lymphocyte Nonresponsiveness: FasL/Fas-Mediated Inhibition of CD4+ and CD8+ Antiviral T Cells by Viral Antigen-Positive Veto Cells , 1999, Journal of Virology.

[21]  N. Kadowaki,et al.  Reciprocal control of T helper cell and dendritic cell differentiation. , 1999, Science.

[22]  Z. Huang,et al.  Immunoregulatory role of CD8alpha in the veto effect. , 1999, Transplantation.

[23]  A. Sharpe,et al.  The role of CD80, CD86, and CTLA4 in alloimmune responses and the induction of long-term allograft survival. , 1999, Journal of immunology.

[24]  Y. Reisner,et al.  Tolerance induction by megadose stem cell transplants: synergism between SCA-1+ Lin- cells and nonalloreactive T cells. , 1998, Transplantation proceedings.

[25]  M. Martelli,et al.  Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. , 1998, The New England journal of medicine.

[26]  Ethan M. Shevach,et al.  CD4+CD25+ Immunoregulatory T Cells Suppress Polyclonal T Cell Activation In Vitro by Inhibiting Interleukin 2 Production , 1998, The Journal of experimental medicine.

[27]  A. Berrebi,et al.  Tolerance induction by "megadose" hematopoietic transplants: donor-type human CD34 stem cells induce potent specific reduction of host anti-donor cytotoxic T lymphocyte precursors in mixed lymphocyte culture. , 1998, Transplantation.

[28]  B. Hall,et al.  Treatment with interleukin-4 prolongs allogeneic neonatal heart graft survival by inducing T helper 2 responses. , 1998, Transplantation.

[29]  J. D. de Vries,et al.  Inhibitory and stimulatory effects of IL-10 on human CD8+ T cells. , 1998, Journal of immunology.

[30]  E. Simpson,et al.  An essential role for Fas ligand in transplantation tolerance induced by donor bone marrow , 1998, Nature Medicine.

[31]  Hervé Groux,et al.  A CD4+T-cell subset inhibits antigen-specific T-cell responses and prevents colitis , 1997, Nature.

[32]  P. Henkart,et al.  Different Interleukin-1β Converting Enzyme (ICE) Family Protease Requirements for the Apoptotic Death of T Lymphocytes Triggered by Diverse Stimuli , 1996, The Journal of experimental medicine.

[33]  E. Plow,et al.  Overlapping, but Not Identical, Sites Are Involved in the Recognition of C3bi, Neutrophil Inhibitory Factor, and Adhesive Ligands by the αMβ2 Integrin* , 1996, The Journal of Biological Chemistry.

[34]  R. Noelle,et al.  Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[36]  F. Aversa,et al.  Successful engraftment of T-cell-depleted haploidentical "three-loci" incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. , 1994, Blood.

[37]  R. Lechler,et al.  Anergic T cells as suppressor cells in vitro. , 1994, Science.

[38]  J. Thomas,et al.  A role for transforming growth factor-beta in the veto mechanism in transplant tolerance. , 1994, Transplantation.

[39]  S. Sambhara,et al.  Reduction of CTL antipeptide response mediated by CD8+ cells whose class I MHC can bind the peptide. , 1994, Journal of immunology.

[40]  G. Pierce,et al.  Do donor cells function as veto cells in the induction and maintenance of tolerance across an MHC disparity in mixed lymphoid radiation chimeras? , 1993, Transplantation.

[41]  D. Kioussis,et al.  "Infectious" transplantation tolerance , 1993, Science.

[42]  G. Pierce,et al.  Thy 1+ donor cells function as veto cells in the maintenance of tolerance across a major histocompatibility complex disparity in mixed-lymphoid radiation chimeras. , 1993, Transplantation proceedings.

[43]  P. Linsley,et al.  Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. , 1992, Science.

[44]  J. Allison,et al.  CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones , 1992, Nature.

[45]  P. Henkart,et al.  Clonal deletion of postthymic T cells: veto cells kill precursor cytotoxic T lymphocytes , 1992, The Journal of experimental medicine.

[46]  M. Claesson,et al.  Veto-like down-regulation of T helper cell reactivity in vivo by injection of semi-allogeneic spleen cells. , 1991, Immunology letters.

[47]  S. Sambhara,et al.  Programmed cell death of T cells signaled by the T cell receptor and the alpha 3 domain of class I MHC. , 1991, Science.

[48]  T. Mosmann,et al.  The role of IL-10 in crossregulation of TH1 and TH2 responses. , 1991, Immunology today.

[49]  G. Crabtree,et al.  Regulation of interleukin-2 gene enhancer activity by the T cell accessory molecule CD28. , 1991, Science.

[50]  K. Heeg,et al.  Induction of peripheral tolerance to class I major histocompatibility complex (MHC) alloantigens in adult mice: transfused class I MHC- incompatible splenocytes veto clonal responses of antigen-reactive Lyt- 2+ T cells , 1990, The Journal of experimental medicine.

[51]  R. Miller,et al.  Functional heterogeneity in allospecific cytotoxic T lymphocyte clones. I. CTL clones express strong anti-self suppressive activity , 1984, The Journal of experimental medicine.

[52]  H. Rammensee,et al.  Studies on the mechanism of suppression of primary cytotoxic responses by cloned cytotoxic T lymphocytes. , 1984, Journal of immunology.

[53]  J. Strominger,et al.  Three distinct antigens associated with human T-lymphocyte-mediated cytolysis: LFA-1, LFA-2, and LFA-3. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[54]  C. Taswell,et al.  Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. , 1981, Journal of immunology.

[55]  C. Taswell,et al.  Quantitation and Cloning of Cytolytic T Lymphocytes and their Precursors , 1980, Immunological reviews.

[56]  R. Miller,et al.  Cells in bone marrow and in T cell colonies grown from bone marrow can suppress generation of cytotoxic T lymphocytes directed against their self antigens , 1980, The Journal of experimental medicine.

[57]  M. Martelli,et al.  Transplants across human leukocyte antigen barriers. , 2002, Seminars in hematology.

[58]  Y. Reisner,et al.  Induction of donor-type chimerism and transplantation tolerance across major histocompatibility barriers in sublethally irradiated mice by Sca-1(+)Lin(-) bone marrow progenitor cells: synergism with non-alloreactive (host x donor)F(1) T cells. , 1999, Blood.

[59]  H. Waldmann,et al.  How do monoclonal antibodies induce tolerance? A role for infectious tolerance? , 1998, Annual review of immunology.

[60]  J. Thomas,et al.  Kidney allograft tolerance in primates without chronic immunosuppression--the role of veto cells. , 1991, Transplantation.

[61]  M. H. Claësson.  Veto cell H-2 antigens: veto cell activity is restricted by determinants encoded by K, D, and I MHC regions. , 1987, Cellular immunology.

[62]  R. Lyman Ott.,et al.  An introduction to statistical methods and data analysis , 1977 .