Characterization of IFNγ-producing natural killer cells induced by cytomegalovirus reactivation after haploidentical hematopoietic stem cell transplantation

Jin, Fengyan; Lin, Hai; Gao, Sujun; Wang, Heng-Xiang; Yan, Hu; Guo, Jinglong; Hu, Zheng; Jin, Chunhui; Wang, Yongqi; Wang, Zhidong; Zhao, Yuhao; Liu, Yu; Zheng, Xianyou; Tan, Yehui; Li, Wei; Dai, Yun; Yang, Yanping

doi:10.18632/oncotarget.13916

Cited by 21 publications

(26 citation statements)

References 40 publications

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“…Knowing that a low IFN-γ response to phytohemagglutinin (PHA) predicts poor survival [11], I assessed CMV-specific and mitogen-induced IFN-γ release using the same commercial quantiferon-cytomegalovirus assay. Unfortunately, in the quantiferon technique, the interferon immune response after CMV-peptide-laden human leukocyte antigen (HLA) class I stimulation showed higher level than PHA-induced in the first wave of lymphocyte reconstitution (i.e., between 2–11 and 19–01), which of note, was during most intensive CMV reactivation [12].…”

Section: Resultsmentioning

confidence: 99%

CMV-Specific Immune Response—New Patients, New Insight: Central Role of Specific IgG during Infancy and Long-Lasting Immune Deficiency after Allogenic Stem Cell Transplantation

Zdziarski

2019

IJMS

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Although the existing paradigm states that cytomegalovirus (CMV) reactivation is under the control of the cellular immune response, the role of humoral and innate counterparts are underestimated. The study analyzed the host–virus interaction i.e., CMV-immune response evolution during infection in three different clinical situations: (1) immunodeficient CMV-positive human leukocyte antigen (HLA)-matched bone marrow recipients after immunoablative conditioning as well as immunocompetent, (2) adult, and (3) infant with primary immune response. In the first situation, a fast and significant decrease of specific immunity was observed but reconstitution of marrow-derived B and natural killer (NK) cells was observed prior to thymic origin of T cells. The lowest CMV-IgG (93.2 RU/mL) was found just before CMV viremia. It is noteworthy that the sole and exclusive factor of CMV-specific immune response is a residual recipient antibody class IgG. The CMV-quantiferon increase was detected later, but in the first phase, phytohemagglutinin (PHA)-induced IFN-γ release was significantly lower than that of CMV-induced (“indeterminate” results). It corresponds with the increase of NK cells at the top of lymphocyte reconstitution and undetected CMV-specific CD8 cells using a pentamer technique. In immunocompetent adult (CMV-negative donor), the cellular and humoral immune response increased in a parallel manner, but symptoms of CMV mononucleosis persisted until the increase of specific IgG. During infancy, the decrease of the maternal CMV-IgG level to 89.08 RU/mL followed by clinical sequel, i.e., CMV replication, were described. My observations shed light on a unique host-CMV interaction and CMV-IgG role: they indicate that its significant decrease predicts CMV replication. Before primary cellular immune response development, the high level of residual CMV-IgG (about >100 R/mL) from mother or recipient prevents virus reactivation. The innate immune response and NK-dependent IFN-secretion should be further investigated.

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Section: Resultsmentioning

confidence: 99%

CMV-Specific Immune Response—New Patients, New Insight: Central Role of Specific IgG during Infancy and Long-Lasting Immune Deficiency after Allogenic Stem Cell Transplantation

Zdziarski

2019

IJMS

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“…This CMV-induced memory-like NK-cell population is characterized by low expressionof CD56, expression of CD57, lack of the inhibitory NKG2a receptor, and expression of the activating heterodimeric receptor CD94-NKG2C ( 20 , 21 ). The memory-associated features of these CMV-induced NK include secondary expansion and enhanced capacity to produce IFN-γ upon CMV reactivation ( 20 , 22 , 23 ). Once induced, their expansion is not limited to CMV reactivation, as stimulation via the low affinity Fc receptor IIIa (CD16) by IgG, as well as pro-inflammatory cytokines, can contribute to the expansion, persistence, and functional properties of CMV-induced memory-like NK cells ( 21 , 24 , 25 ).…”

Section: Possible Mechanisms Of Anti-leukemic Effects Of CMV After Almentioning

confidence: 99%

“…Alternatively, in partially HLA-mismatched HSCT, the anti-leukemic effect may be related to the general mechanism of NK-cell self-tolerance, which is mediated by inhibitory receptors, such as killer cell immunoglobulin-like receptors (KIR), that recognize self-MHC class I molecules. According to the “missing-self hypothesis,” recipient AML cells can be the target for cytotoxicity of donor-derived NKG2C + NK cells, induced upon CMV infection, as they lack donor HLA molecules ( 23 ).…”

Section: Possible Mechanisms Of Anti-leukemic Effects Of CMV After Almentioning

confidence: 99%

Potential Beneficial Effects of Cytomegalovirus Infection after Transplantation

et al. 2018

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Cytomegalovirus (CMV) infection can cause significant complications after transplantation, but recent emerging data suggest that CMV may paradoxically also exert beneficial effects in two specific allogeneic transplant settings. These potential benefits have been underappreciated and are therefore highlighted in this review. First, after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) using T-cell and natural killer (NK) cell-replete grafts, CMV reactivation is associated with protection from leukemic relapse. This association was not observed for other hematologic malignancies. This anti-leukemic effect might be mediated by CMV-driven expansion of donor-derived memory-like NKG2C+ NK and Vδ2negγδ T-cells. Donor-derived NK cells probably recognize recipient leukemic blasts by engagement of NKG2C with HLA-E and/or by the lack of donor (self) HLA molecules. Vδ2negγδ T cells probably recognize as yet unidentified antigens on leukemic blasts via their TCR. Second, immunological imprints of CMV infection, such as expanded numbers of Vδ2negγδ T cells and terminally differentiated TCRαβ+ T cells, as well as enhanced NKG2C gene expression in peripheral blood of operationally tolerant liver transplant patients, suggest that CMV infection or reactivation may be associated with liver graft acceptance. Mechanistically, poor alloreactivity of CMV-induced terminally differentiated TCRαβ+ T cells and CMV-induced IFN-driven adaptive immune resistance mechanisms in liver grafts may be involved. In conclusion, direct associations indicate that CMV reactivation may protect against AML relapse after allogeneic HSCT, and indirect associations suggest that CMV infection may promote allograft acceptance after liver transplantation. The causative mechanisms need further investigations, but are probably related to the profound and sustained imprint of CMV infection on the immune system.

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“…Additional studies are needed to clarify if these instances of NKG2C + NK expansion in the absence of acute HCMV are due to cross-reactive antigens (either viral or viral-induced host) between CMV and these other infections, to the specific inflammatory milieu elicited, to (subclinical) CMV reactivation, or to some combination of these factors. Several studies have suggested that CMV reactivation and the subsequent expansion of NKG2C + NK cells may improve clinical outcomes for leukemia patients [77–80], and a recent study found that among CMV-seropositive patients newly infected with HIV, a higher frequency of NKG2C + CD57 + NK cells correlated with lower HIV viral load and more rapidly reaching undetectable viremia levels after combination antiretroviral therapy [81]. It will be of great interest to determine what clinical benefits there may be to patients that experience an expansion of the NKG2C + NK cell population in the setting of antiviral immunity against additional infections.…”

Section: Antigen-dependent Generation Of Nk Cell Memorymentioning

confidence: 99%

Memory responses of natural killer cells

Geary

Sun

2017

Seminars in Immunology

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Natural killer (NK) cells have traditionally been classified as a cellular component of the innate immune system, given their ability to rapidly produce effector cytokines and kill infected or transformed cells without prior exposure. More recently, NK cells have been shown to possess features of adaptive immunity such as clonal expansion, longevity, and robust recall responses. NK cell memory can be broadly divided into two categories: antigen-specific and antigen-independent. In the first case, exposure to certain viral or hapten stimuli endows NK cells with antigen-specific immunological memory, similar to T and B cells. In the second case, exposure of NK cells to specific cytokine milieus can imprint long-lasting changes on effector functions, resulting in antigen-independent memory-like NK cells. In this review, we discuss the various conditions that promote generation of these two categories of memory NK cells, and the mechanistic requirements underlying these processes.

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Characterization of IFNγ-producing natural killer cells induced by cytomegalovirus reactivation after haploidentical hematopoietic stem cell transplantation

Cited by 21 publications

References 40 publications

CMV-Specific Immune Response—New Patients, New Insight: Central Role of Specific IgG during Infancy and Long-Lasting Immune Deficiency after Allogenic Stem Cell Transplantation

CMV-Specific Immune Response—New Patients, New Insight: Central Role of Specific IgG during Infancy and Long-Lasting Immune Deficiency after Allogenic Stem Cell Transplantation

Potential Beneficial Effects of Cytomegalovirus Infection after Transplantation

Memory responses of natural killer cells

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