title: Latent cytomegalovirus infection enhances anti-tumour cytotoxicity through accumulation of NKG2C+ NK cells in healthy humans.
abstract: Cytomegalovirus (CMV) infection markedly expands NKG2C+/NKG2A- NK cells, which are potent killers of infected cells expressing human leucocyte antigen (HLA)-E. As HLA-E is also over-expressed in several haematological malignancies and CMV has been linked to a reduced risk of leukaemic relapse, we determined the impact of latent CMV infection on NK cell cytotoxicity against four tumour target cell lines with varying levels of HLA-E expression. NK cell cytotoxicity against K562 (leukaemia origin) and U266 (multiple myeloma origin) target cells was strikingly greater in healthy CMV-seropositive donors than seronegative donors and was associated strongly with target cell HLA-E and NK cell NKG2C expression. NK cell cytotoxicity against HLA-E transfected lymphoma target cells (221.AEH) was ∼threefold higher with CMV, while NK cell cytotoxicity against non-transfected 721.221 cells was identical between the CMV groups. NK cell degranulation (CD107a(+) ) and interferon (IFN)-γ production to 221.AEH cells was localized almost exclusively to the NKG2C subset, and antibody blocking of NKG2C completely eliminated the effect of CMV on NK cell cytotoxicity against 221.AEH cells. Moreover, 221.AEH feeder cells and interleukin (IL)-15 were found to expand NKG2C(+) /NKG2A(-) NK cells preferentially from CMV-seronegative donors and increase NK cell cytotoxicity against HLA-E(+) tumour cell lines. We conclude that latent CMV infection enhances NK cell cytotoxicity through accumulation of NKG2C(+) NK cells, which may be beneficial in preventing the initiation and progression of haematological malignancies characterized by high HLA-E expression.
authors.affiliation: Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Bigley
authors.affiliation: Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Rezvani
authors.affiliation: Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Shah
authors.affiliation: Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: T
authors.initials: T
authors.lastname: Sekine
authors.affiliation: Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Balneger
authors.affiliation: Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Pistillo
authors.affiliation: Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Agha
authors.affiliation: Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kunz
authors.affiliation: Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: O'Connor
authors.affiliation: Program for Cell Enhancement and Technologies for Immunotherapy, Sheikh Zayed Institute for Pediatric Surgical Innovation and Center for Cancer and Immunology Research, Children's National Health System, Washington, DC, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Bollard
authors.affiliation: Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Simpson
mesh_terms: D000293:Adolescent; D000328:Adult; D018959:CD57 Antigens / Q000276:immunology; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D005260:Female; D064368:Healthy Volunteers; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000032:analysis* / Q000276:immunology; D017735:Virus Latency; D055815:Young Adult; D000097625:HLA-E Antigens
chemical_list: D018959:CD57 Antigens; D015395:Histocompatibility Antigens Class I; D055654:NK Cell Lectin-Like Receptor Subfamily C; D000097625:HLA-E Antigens; C527054:KLRC1 protein, human; C527059:KLRC2 protein, human
keywords: 221 AEH; CD158; CD57; K562; NKG2A; U266; leukaemia; lymphoma; multiple myeloma