The role of Vδ2-negative γδ T cells during cytomegalovirus reactivation in recipients of allogeneic stem cell transplantation.

Reactivation of cytomegalovirus (CMV) remains a serious complication after allogeneic stem cell transplantation, but the role of γδ T cells is undefined. We have studied the immune reconstitution of Vδ2negative (Vδ2neg) γδ T cells, including Vδ1 and Vδ3 subsets and Vδ2positive (Vδ2pos) γδ T cells in 40 patients during the first 24 months after stem cell transplantation. Significant long-term expansions of Vδ2neg but not Vδ2pos γδ T cells were observed during CMV reactivation early after transplantation, suggesting direct involvement of γδ T cells in anti-CMV immune responses. Similarly, significantly higher numbers of Vδ2neg γδ T cells were detected in CMV-seropositive healthy persons compared with seronegative donors; the absolute numbers of Vδ2pos cells were not significantly different. The expansion of Vδ2neg γδ T cells appeared to be CMV-related because it was absent in CMV-negative/Epstein-Barr virus-positive patients. T-cell receptor-δ chain determining region 3 spectratyping of Vδ2neg γδ T cells in healthy subjects and patients showed restricted clonality. Polyclonal Vδ2neg cell lines generated from CMV-seropositive healthy donors and from a recipient of a graft from a CMV-positive donor lysed CMV-infected targets in all cases. Our study shows new evidence for role of γδ T cells in the immune response to CMV reactivation in transplantation recipients.

[1]  M. Goldman,et al.  Human cytomegalovirus elicits fetal γδ T cell responses in utero , 2010, The Journal of experimental medicine.

[2]  J. Moreau,et al.  Long-term expansion of effector/memory Vdelta2-gammadelta T cells is a specific blood signature of CMV infection. , 2008, Blood.

[3]  M. Hirokawa,et al.  Skewed T cell receptor repertoire of Vδ1+ γδ T lymphocytes after human allogeneic haematopoietic stem cell transplantation and the potential role for Epstein–Barr virus‐infected B cells in clonal restriction , 2007 .

[4]  M. Gobbi,et al.  Expansion of Vdelta1 T lymphocytes producing IL-4 in low-grade non-Hodgkin lymphomas expressing UL-16-binding proteins. , 2007, Blood.

[5]  D. Raulet,et al.  Development and selection of γδ T cells , 2007 .

[6]  J. North,et al.  Tumor-Primed Human Natural Killer Cells Lyse NK-Resistant Tumor Targets: Evidence of a Two-Stage Process in Resting NK Cell Activation1 , 2007, The Journal of Immunology.

[7]  A. Hayday,et al.  Early events in the thymus affect the balance of effector and regulatory T cells , 2006, Nature.

[8]  P. Molnar,et al.  Earth science: Palaeo-altimetry of Tibet , 2006, Nature.

[9]  M. Büchler,et al.  Soluble MIC is elevated in the serum of patients with pancreatic carcinoma diminishing γδ T cell cytotoxicity , 2006 .

[10]  C. Sutherland,et al.  ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15. , 2006, Blood.

[11]  Hui Chen,et al.  Vdelta1 T cell receptor binds specifically to MHC I chain related A: molecular and biochemical evidences. , 2006, Biochemical and biophysical research communications.

[12]  H. de la Salle,et al.  Shared reactivity of Vδ2neg γδ T cells against cytomegalovirus-infected cells and tumor intestinal epithelial cells , 2005, The Journal of experimental medicine.

[13]  M. Wilhelm,et al.  Anti-lymphoma effect of γδ T cells , 2005 .

[14]  A. Hayday,et al.  Gammadelta T cell development--having the strength to get there. , 2005, Current opinion in immunology.

[15]  C. Agrati,et al.  Antiviral reactivities of γδ T cells , 2005, Microbes and Infection.

[16]  M. Gobbi,et al.  Vδ1 T Lymphocytes from B-CLL Patients Recognize ULBP3 Expressed on Leukemic B Cells and Up-Regulated by Trans-Retinoic Acid , 2004, Cancer Research.

[17]  R. Khanna,et al.  Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments. , 2004, The Lancet. Infectious diseases.

[18]  N. Malats,et al.  Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. , 2004, Blood.

[19]  H. Jomaa,et al.  Integrated immune responses to infection – cross‐talk between human γδ T cells and dendritic cells , 2004 .

[20]  A. Poggi,et al.  Migration of V delta 1 and V delta 2 T cells in response to CXCR3 and CXCR4 ligands in healthy donors and HIV-1-infected patients: competition by HIV-1 Tat. , 2004, Blood.

[21]  P. Moss,et al.  Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines , 2003, The Lancet.

[22]  H. Rammensee,et al.  Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. , 2003, Blood.

[23]  E. Remmerswaal,et al.  Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. , 2003, Blood.

[24]  C. Agrati,et al.  Innate T-Cell Immunity in HIV Infections: The Role of Vg9Vd2 T Lymphocytes , 2002 .

[25]  J. Moreau,et al.  Cytomegalovirus Infection in Transplant Recipients Resolves When Circulating γδ T Lymphocytes Expand, Suggesting a Protective Antiviral Role , 2001 .

[26]  Lisheng Wang,et al.  Vγ2Vδ2 T-cell receptor-mediated recognition of aminobisphosphonates , 2001 .

[27]  T. Spies,et al.  MICA Engagement by Human Vγ2Vδ2 T Cells Enhances Their Antigen-Dependent Effector Function , 2001 .

[28]  R. Armitage,et al.  ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. , 2001, Immunity.

[29]  M. Roederer,et al.  11-color, 13-parameter flow cytometry: Identification of human naive T cells by phenotype, function, and T-cell receptor diversity , 2001, Nature Medicine.

[30]  C. Craddock,et al.  Cytomegalovirus seropositivity adversely influences outcome after T‐depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft‐versus‐host disease prophylaxis , 2001, British journal of haematology.

[31]  J. Bell,et al.  Functional Heterogeneity and High Frequencies of Cytomegalovirus-Specific CD8+ T Lymphocytes in Healthy Seropositive Donors , 2000, Journal of Virology.

[32]  M. Hirokawa,et al.  Reconstitution of γδ T cell repertoire diversity after human allogeneic hematopoietic cell transplantation and the role of peripheral expansion of mature T cell population in the graft , 2000, Bone Marrow Transplantation.

[33]  V. Kuenen-Boumeester,et al.  Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell-depleted stem cell transplantation. , 2000, Blood.

[34]  M. Weekes,et al.  Large clonal expansions of human virus‐specific memory cytotoxic T lymphocytes within the CD57+ CD28– CD8+ T‐cell population , 1999, Immunology.

[35]  M. Bonneville,et al.  Expansion of circulating Vγ9 / Vδ1 T cells in a patient with a syndrome of recurrent fever: evidence for an unusual antigen‐driven process leading to selection of recurrent motifs within TCR junctional loops of diverse lengths , 1999, European journal of immunology.

[36]  M. Bonneville,et al.  Implication of γδ T cells in the human immune response to cytomegalovirus , 1999 .

[37]  M. Bonneville,et al.  Implication of gammadelta T cells in the human immune response to cytomegalovirus. , 1999, The Journal of clinical investigation.

[38]  A. Necker,et al.  Immunophenotypic and immunogenotypic characteristics of TCRγδ+ T cell acute lymphoblastic leukemia , 1999, Leukemia.

[39]  E. Helm,et al.  Increase in Vδ1+γδ T cells in the peripheral blood and bone marrow as a selective feature of HIV‐1 but not other virus infections , 1998 .

[40]  Y. Kaneko,et al.  Evidence for B cell-mediated activation of V delta 1+ T lymphocytes during progression of HIV infection. , 1997, Journal of immunology.

[41]  S. Kaufmann,et al.  gamma/delta and other unconventional T lymphocytes: what do they see and what do they do? , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[42]  R. Krance,et al.  Gamma delta T lymphocyte regeneration after T lymphocyte-depleted bone marrow transplantation from mismatched family members or matched unrelated donors. , 1996, Bone marrow transplantation.

[43]  P. Lehner,et al.  CD8highCD57+ T lymphocytes in normal, healthy individuals are oligoclonal and respond to human cytomegalovirus. , 1995, Journal of immunology.

[44]  F. Poccia,et al.  CDR3-independent gamma delta V delta 1+ T cell expansion in the peripheral blood of HIV-infected persons. , 1995, Journal of immunology.

[45]  G. Klein,et al.  Functional and molecular characterization of B cell‐responsive Vδ1+ γδ T cells , 1994 .

[46]  P. Tak,et al.  A Subset of Vδ1+ T Cells Proliferates in Response to Epstein‐Barr Virus‐Transformed B Cell Lines In Vitro , 1993 .

[47]  N. Moore,et al.  Cytomegalovirus-induced gammadelta T cells associate with reduced cancer risk after kidney transplantation. , 2010, Journal of the American Society of Nephrology : JASN.

[48]  S. Mackinnon,et al.  Adoptive cellular therapy for cytomegalovirus infection following allogeneic stem cell transplantation using virus-specific T cells. , 2008, Blood cells, molecules & diseases.

[49]  M. Hirokawa,et al.  Skewed T cell receptor repertoire of Vdelta1(+) gammadelta T lymphocytes after human allogeneic haematopoietic stem cell transplantation and the potential role for Epstein-Barr virus-infected B cells in clonal restriction. , 2007, Clinical and experimental immunology.

[50]  D. Raulet,et al.  Development and selection of gammadelta T cells. , 2007, Immunological reviews.

[51]  M. Büchler,et al.  Soluble MIC is elevated in the serum of patients with pancreatic carcinoma diminishing gammadelta T cell cytotoxicity. , 2006, International journal of cancer.

[52]  M. Wilhelm,et al.  Anti-lymphoma effect of gammadelta T cells. , 2005, Leukemia & lymphoma.

[53]  A. Burroughs,et al.  Kinetics of cytomegalovirus load decrease in solid-organ transplant recipients after preemptive therapy with valganciclovir. , 2005, Journal of Infectious Diseases.

[54]  H. Jomaa,et al.  Integrated immune responses to infection - cross-talk between human gammadelta T cells and dendritic cells. , 2004, Immunology.

[55]  M. Gobbi,et al.  Vdelta1 T lymphocytes from B-CLL patients recognize ULBP3 expressed on leukemic B cells and up-regulated by trans-retinoic acid. , 2004, Cancer research.

[56]  S. Carding,et al.  Gammadelta T cells: functional plasticity and heterogeneity. , 2002, Nature reviews. Immunology.

[57]  C. Agrati,et al.  Innate T-cell immunity in HIV infection: the role of Vgamma9Vdelta2 T lymphocytes. , 2002, Current molecular medicine.

[58]  J. Moreau,et al.  Cytomegalovirus infection in transplant recipients resolves when circulating gammadelta T lymphocytes expand, suggesting a protective antiviral role. , 2001, The Journal of infectious diseases.

[59]  C. Kuijl,et al.  MICA engagement by human Vgamma2Vdelta2 T cells enhances their antigen-dependent effector function. , 2001, Immunity.

[60]  C. Agrati,et al.  Vδ1T Lymphocytes Expressing a Th1 Phenotype Are the Major γδ T Cell Subset Infiltrating the Liver of HCV-infected Persons , 2001, Molecular medicine.

[61]  J. Bukowski,et al.  Vgamma2Vdelta2 T-cell receptor-mediated recognition of aminobisphosphonates. , 2001, Blood.

[62]  A. Hayday.  [gamma][delta] cells: a right time and a right place for a conserved third way of protection. , 2000, Annual review of immunology.

[63]  J. V. van Dongen,et al.  Immunophenotypic and immunogenotypic characteristics of TCRgammadelta+ T cell acute lymphoblastic leukemia. , 1999, Leukemia.

[64]  E. Helm,et al.  Increase in Vdelta1+ gammadelta T cells in the peripheral blood and bone marrow as a selective feature of HIV-1 but not other virus infections. , 1998, British journal of haematology.

[65]  G. Klein,et al.  Functional and molecular characterization of B cell-responsive V delta 1+ gamma delta T cells. , 1994, European journal of immunology.

[66]  P. Tak,et al.  A subset of V delta 1+ T cells proliferates in response to Epstein-Barr virus-transformed B cell lines in vitro. , 1993, Scandinavian journal of immunology.