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PMID: 24319201 Published · ppublish English Journal Article Review

Natural killer cells and regulatory T cells: how to manipulate a graft for optimal GVL.

Hematology. American Society of Hematology. Education Program ·Vol. 2013 ·2013-00-00 ·Pages 335-41

Verneris MR

Abstract

Two of the major complications that limit the efficacy of allogeneic hematopoietic cell transplantation (allo-HCT) are disease relapse and GVHD. Due to their rapid recovery early after allo-HCT and their ability to kill malignant targets without prior exposure, natural killer (NK) cells have been considered one of the main effector cells that mediate early GVL reactions. Conversely, regulatory T ells (Tregs) have proven to be critical in facilitating self-tolerance. Both murine and human studies have demonstrated a significant role for Tregs in the modulation of GVHD after allo-HCT. This article reviews the mechanisms of how these 2 cell types carry out these functions, focusing on the post-allo-HCT period. Surprisingly, relatively few studies have addressed how Tregs and NK cells interact with one another and whether these interactions are antagonistic. Although preclinical studies suggest active cross-talk between NK cells and Tregs, early clinical studies have not shown a detrimental impact of Treg therapy on relapse. Despite this, interruption of tolerogenic signals may enhance the efficacy of NK effector functions. Methods to transiently impair Treg functions and augment NK cell alloreactivity will be discussed.

MeSH Terms
Allografts Cell Communication/immunology Graft vs Leukemia Effect/immunology Hematopoietic Stem Cell Transplantation Humans Killer Cells, Natural/immunology,pathology Self Tolerance T-Lymphocytes, Regulatory/immunology,pathology
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Verneris Michael R
1Division of Pediatric Blood and Marrow Transplantation, University of Minnesota Amplatz Children's Hospital, Minneapolis, MN.
References (60)
60 references, click to expand
  1. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics.
    Blood. 2011 Jan 20;117(3):1061-70 PMID: 20952687
  2. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner.
    J Exp Med. 2005 Oct 17;202(8):1075-85 PMID: 16230475
  3. Postallograft lenalidomide induces strong NK cell-mediated antimyeloma activity and risk for T cell-mediated GvHD: Results from a phase I/II dose-finding study.
    Exp Hematol. 2013 Feb;41(2):134-142.e3 PMID: 23085463
  4. Massive ex vivo expansion of human natural regulatory T cells (T(regs)) with minimal loss of in vivo functional activity.
    Sci Transl Med. 2011 May 18;3(83):83ra41 PMID: 21593401
  5. Human T regulatory cell therapy: take a billion or so and call me in the morning.
    Immunity. 2009 May;30(5):656-65 PMID: 19464988
  6. Clinical-grade ex vivo-expanded human natural killer cells up-regulate activating receptors and death receptor ligands and have enhanced cytolytic activity against tumor cells.
    Cytotherapy. 2009;11(3):341-55 PMID: 19308771
  7. Natural killer cells prevent CD28-mediated Foxp3 transcription in CD4+CD25- T lymphocytes.
    Exp Hematol. 2007 Mar;35(3):416-25 PMID: 17309822
  8. Association of bone marrow natural killer cell dose with neutrophil recovery and chronic graft-versus-host disease after HLA identical sibling bone marrow transplants.
    Br J Haematol. 2007 Jul;138(1):101-9 PMID: 17555453
  9. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects.
    Blood. 2010 May 27;115(21):4293-301 PMID: 20233969
  10. Foxp3+ regulatory T cells: differentiation, specification, subphenotypes.
    Nat Immunol. 2009 Jul;10(7):689-95 PMID: 19536194
  11. NK cells lyse T regulatory cells that expand in response to an intracellular pathogen.
    J Immunol. 2008 Feb 1;180(3):1729-36 PMID: 18209070
  12. The graft content of donor T cells expressing gamma delta TCR+ and CD4+foxp3+ predicts the risk of acute graft versus host disease after transplantation of allogeneic peripheral blood stem cells from unrelated donors.
    Clin Cancer Res. 2007 May 15;13(10):2916-22 PMID: 17504991
  13. Regulatory T cells in stem cell transplantation: strategies and first clinical experiences.
    Curr Opin Immunol. 2011 Oct;23(5):679-84 PMID: 21802270
  14. Coordinated acquisition of inhibitory and activating receptors and functional properties by developing human natural killer cells.
    Blood. 2006 Dec 1;108(12):3824-33 PMID: 16902150
  15. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells.
    PLoS One. 2012;7(1):e30264 PMID: 22279576
  16. Human tumor-induced and naturally occurring Treg cells differentially affect NK cells activated by either IL-2 or target cells.
    Eur J Immunol. 2011 Dec;41(12):3564-73 PMID: 21905023
  17. Human natural killer cell development.
    Immunol Rev. 2006 Dec;214:56-72 PMID: 17100876
  18. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells.
    Cancer Immunol Immunother. 2009 Jul;58(7):1033-45 PMID: 19009291
  19. Severe herpesvirus infections in an adolescent without natural killer cells.
    N Engl J Med. 1989 Jun 29;320(26):1731-5 PMID: 2543925
  20. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia.
    Blood. 2010 Oct 7;116(14):2411-9 PMID: 20581313
  21. Early lymphocyte recovery and outcomes after umbilical cord blood transplantation (UCBT) for hematologic malignancies.
    Biol Blood Marrow Transplant. 2011 Jun;17(6):831-40 PMID: 20831896
  22. Licensing of natural killer cells by host major histocompatibility complex class I molecules.
    Nature. 2005 Aug 4;436(7051):709-13 PMID: 16079848
  23. IL-2-dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells.
    J Exp Med. 2013 Jun 3;210(6):1167-78 PMID: 23650441
  24. HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1.
    N Engl J Med. 2012 Aug 30;367(9):805-16 PMID: 22931314
  25. Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4120-5 PMID: 12646700
  26. Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients.
    Blood. 2011 Aug 4;118(5):1402-12 PMID: 21540462
  27. Interaction between natural killer cells and regulatory T cells: perspectives for immunotherapy.
    Cell Mol Immunol. 2013 May;10(3):222-9 PMID: 23524654
  28. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants.
    Science. 2002 Mar 15;295(5562):2097-100 PMID: 11896281
  29. Inhibitory KIR-HLA receptor-ligand mismatch in autologous haematopoietic stem cell transplantation for solid tumour and lymphoma.
    Br J Cancer. 2007 Aug 20;97(4):539-42 PMID: 17667923
  30. Impact of cytomegalovirus (CMV) reactivation after umbilical cord blood transplantation.
    Biol Blood Marrow Transplant. 2010 Feb;16(2):215-22 PMID: 19786112
  31. Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation.
    J Clin Invest. 2010 May;120(5):1479-93 PMID: 20389017
  32. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function.
    Blood. 2012 Mar 15;119(11):2665-74 PMID: 22180440
  33. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells.
    Blood. 2005 Jul 1;106(1):376-83 PMID: 15755898
  34. Mechanisms of foxp3+ T regulatory cell-mediated suppression.
    Immunity. 2009 May;30(5):636-45 PMID: 19464986
  35. CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia.
    Blood. 2013 Aug 15;122(7):1316-24 PMID: 23744585
  36. NK cells and Treg cells: a fascinating dance cheek to cheek.
    Eur J Immunol. 2008 Nov;38(11):2942-5 PMID: 18979513
  37. Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56(bright) subset.
    Blood. 2013 Apr 4;121(14):2669-77 PMID: 23365458
  38. Regulatory T cells in stem cell transplantation: main characters or walk-on actors?
    Crit Rev Oncol Hematol. 2012 Oct;84(1):18-25 PMID: 22386896
  39. CD4+CD25+ regulatory T cell depletion improves the graft-versus-tumor effect of donor lymphocytes after allogeneic hematopoietic stem cell transplantation.
    Sci Transl Med. 2010 Jul 21;2(41):41ra52 PMID: 20650872
  40. Decreased infections in recipients of unrelated donor hematopoietic cell transplantation from donors with an activating KIR genotype.
    Biol Blood Marrow Transplant. 2010 Aug;16(8):1155-61 PMID: 20197104
  41. Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation.
    J Immunol. 2007 Jan 1;178(1):85-94 PMID: 17182543
  42. Expansion of a unique CD57⁺NKG2Chi natural killer cell subset during acute human cytomegalovirus infection.
    Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14725-32 PMID: 21825173
  43. IL-2-dependent adaptive control of NK cell homeostasis.
    J Exp Med. 2013 Jun 3;210(6):1179-87 PMID: 23650439
  44. Influence of transplanted dose of CD56+ cells on development of graft-versus-host disease in patients receiving G-CSF-mobilized peripheral blood progenitor cells from HLA-identical sibling donors.
    Bone Marrow Transplant. 2003 Sep;32(5):505-10 PMID: 12942097
  45. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer.
    Blood. 2005 Apr 15;105(8):3051-7 PMID: 15632206
  46. Interleukin-2 and regulatory T cells in graft-versus-host disease.
    N Engl J Med. 2011 Dec 1;365(22):2055-66 PMID: 22129252
  47. FOXP3: of mice and men.
    Annu Rev Immunol. 2006;24:209-26 PMID: 16551248
  48. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis.
    Annu Rev Immunol. 2001;19:197-223 PMID: 11244035
  49. Generation and large-scale expansion of human inducible regulatory T cells that suppress graft-versus-host disease.
    Am J Transplant. 2011 Jun;11(6):1148-57 PMID: 21564534
  50. Functions of natural killer cells.
    Nat Immunol. 2008 May;9(5):503-10 PMID: 18425107
  51. Decrease of CD4(+)CD25(+) regulatory T cells and TGF-beta at early immune reconstitution is associated to the onset and severity of graft-versus-host disease following allogeneic haematogenesis stem cell transplantation.
    Leuk Res. 2010 Sep;34(9):1158-68 PMID: 20409584
  52. Lymphocyte recovery after allogeneic bone marrow transplantation predicts risk of relapse in acute lymphoblastic leukemia.
    Leukemia. 2003 Sep;17(9):1865-70 PMID: 12970788
  53. Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2.
    J Exp Med. 2013 Jun 3;210(6):1153-65 PMID: 23650440
  54. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT.
    Blood. 2006 Aug 15;108(4):1291-7 PMID: 16627754
  55. NK cell receptors.
    Annu Rev Immunol. 1998;16:359-93 PMID: 9597134
  56. Activation of human NK cells by plasmacytoid dendritic cells and its modulation by CD4+ T helper cells and CD4+ CD25hi T regulatory cells.
    Eur J Immunol. 2005 Aug;35(8):2452-8 PMID: 15997468
  57. CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer.
    J Immunol. 2006 Feb 1;176(3):1582-7 PMID: 16424187
  58. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation.
    Blood. 2011 Apr 7;117(14):3921-8 PMID: 21292771
  59. Acute but not chronic graft-versus-host disease is associated with a reduction of circulating CD4(+)CD25 (high)CD127 (low/-) regulatory T cells.
    Ann Hematol. 2011 Feb;90(2):213-8 PMID: 20859740
  60. Regulatory T cells: customizing for the clinic.
    Sci Transl Med. 2011 May 18;3(83):83ps19 PMID: 21593399
Article Info
Journal
Hematology. American Society of Hematology. Education Program
Abbr.
Hematology Am Soc Hematol Educ Program
ISSN
1520-4383
DOI
10.1182/asheducation-2013.1.335
Published
2013-00-00
Pages
335-41
Language
English
Region
United States
NLM ID
100890099
PMCID
PMC4020013
Subset
IM
Grants
NIAID NIH HHS · R01 AI100879 · United States
External Links
PubMed source DOI: 10.1182/asheducation-2013.1.335 PMC Full Text View journal details
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