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Human cytomegalovirus (CMV)-induced memory-like NKG2C(+) NK cells are transplantable and expand in vivo in response to recipient CMV antigen.

ABSTRACT: We have previously shown that NKG2C(+) NK cells from CMV naive umbilical cord blood grafts expand preferentially in recipients after CMV reactivation, representing a primary NK cell response after hematopoietic cell transplantation. In this study, recipients of adult donor hematopoietic cell transplantation were assessed to evaluate the role of donor/recipient CMV serostatus on the expression and function of NKG2C(+) NK cells to determine responses to secondary CMV events. Expansion of NKG2C(+) NK cells was seen following clinical CMV reactivation. However, they also expanded in the absence of detectable CMV viremia when both the donor and recipient were CMV seropositive. Upregulation of NKG2C was observed in NK cells from CMV-positive recipients receiving grafts from CMV-seropositive or -seronegative donors. These in vivo-expanded NKG2C(+) NK cells had an increased capacity for target cell-induced cytokine production, expressed an inhibitory killer Ig-like receptor for self-HLA and preferentially acquired CD57. Most importantly, NKG2C(+) NK cells transplanted from seropositive donors exhibit heightened function in response to a secondary CMV event compared with NKG2C(+) NK cells from seronegative donors. We conclude that NKG2C(+) memory-like NK cells are transplantable and require active or latent (subclinical) expression of CMV Ag in the recipient for clonal expansion of NK cells previously exposed to CMV in the donor.

SUBMITTER: Foley B

PROVIDER: S-EPMC3490031 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Human cytomegalovirus (CMV)-induced memory-like NKG2C(+) NK cells are transplantable and expand in vivo in response to recipient CMV antigen.

Foley Bree B Cooley Sarah S Verneris Michael R MR Curtsinger Julie J Luo Xianghua X Waller Edmund K EK Anasetti Claudio C Weisdorf Daniel D Miller Jeffrey S JS

Journal of immunology (Baltimore, Md. : 1950) 20121017 10

We have previously shown that NKG2C(+) NK cells from CMV naive umbilical cord blood grafts expand preferentially in recipients after CMV reactivation, representing a primary NK cell response after hematopoietic cell transplantation. In this study, recipients of adult donor hematopoietic cell transplantation were assessed to evaluate the role of donor/recipient CMV serostatus on the expression and function of NKG2C(+) NK cells to determine responses to secondary CMV events. Expansion of NKG2C(+) ...[more]

PMID: 23077239

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Project description:Natural killer (NK) cells play a dual role in the defense against viral pathogens by directly lysing infected cells as well as by regulating anti-viral T cell immunity. Infection by human cytomegalovirus (HCMV) promotes a persistent expansion of NKG2C+ adaptive NK cells which have been shown to display enhanced antibody-dependent responses against infected targets and associated to viral control in transplanted patients. Based on gene expression data showing increased transcription of CIITA and several genes related to the MHC class II pathway in adaptive NK cells, we explored their putative capacity for antigen presentation to CD4+ T cells. Phenotypic analysis confirmed a preferential steady-state expression of HLA-DR by circulating NKG2C+ adaptive NK cells in healthy individuals. Expression of HLA-DR in NKG2C+ adaptive NK cells was variable and unrelated to the expression of activation (i.e., CD69 and CD25) or differentiation (i.e., FcRγ chain, CD57) markers, remaining stable over time at the individual level. Incubation of purified NK cells with HCMV complexed with serum specific antibodies induced an up-regulation of surface HLA-DR concomitant to CD16 loss whereas no changes in CD80/CD86 co-stimulatory ligands were detected. In addition, surface CX3CR1 decreased upon antigen-loading while HLA-DR+ NK cells maintained a CCR7-, CXCR3low homing profile. Remarkably, HCMV-loaded purified NK cells activated autologous CD4+ T cells in an HLA-DR dependent manner. The fraction of T lymphocytes activated by antigen-loaded NK cells was smaller than that stimulated by monocyte-derived dendritic cells, corresponding to CD28-negative effector-memory CD4+ T cells with cytotoxic potential. Antigen presentation by NK cells activated a polyfunctional CD4+ T cell response characterized by degranulation (CD107a) and the secretion of Th1 cytokines (IFNγ and TNFα). Overall, our data discloses the capacity of NKG2C+ adaptive NK cells to process and present HCMV antigens to memory CD4+ cytotoxic T cells, directly regulating their response to the viral infection.

Dataset Information

Human cytomegalovirus (CMV)-induced memory-like NKG2C(+) NK cells are transplantable and expand in vivo in response to recipient CMV antigen.

Publications

Human cytomegalovirus (CMV)-induced memory-like NKG2C(+) NK cells are transplantable and expand in vivo in response to recipient CMV antigen.

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