Increased Susceptibility of the CD57− NK Cells Expressing KIR2DL2/3 and NKG2C to iCasp9 Gene Retroviral Transduction and the Relationships with Proliferative Potential, Activation Degree, and Death Induction Response

Palamarchuk, A. I.; Alekseeva, Nadezhda; Streltsova, Maria A.; Ustiuzhanina, Maria O.; Kobyzeva, Polina A.; Erokhina, Sofya A.; Гречихина, М. В.; Boyko, Anna A.; Шустова, О. А.; Sapozhnikov, Alexander M.; Kovalenko, Elena I.

doi:10.3390/ijms222413326

Cited by 4 publications

(3 citation statements)

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“…CD57 − CD56 dim NKG2C + NK cells perform transitional stages in the process of NK cell differentiation and, at the same time, are characterized by a higher proliferative potential and survival. We have also revealed that CD57 − NK cells expressing NKG2C and KIR2DL2/3 are more susceptible to retroviral transduction compared to less differentiated NKG2C − KIR2DL2/3 − cells, which makes CD57 − NKG2C + KIR2DL2/3 + cells a promising source for genetic modification and further therapeutic application [ 47 ]. Therefore, approaches that facilitate the accumulation of CD57 − NKG2C + KIR2DL2/3 + cells are required for generating large numbers of NK cells without losing NKG2C and the inhibitory receptors KIR2DL2/3, which mark cytotoxic mature cells with an increased accumulation of cytotoxic vesicles [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Obtaining Gene-Modified HLA-E-Expressing Feeder Cells for Stimulation of Natural Killer Cells

Alekseeva,

Streltsova,

Vavilova

et al. 2024

Pharmaceutics

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Human cytomegalovirus (HCMV)-specific adaptive NK cells are capable of recognizing viral peptides presented by HLA-E on infected cells via the NKG2C receptor. Using retroviral transduction, we have generated a K562-cell-based line expressing HLA-E in the presence of the HLA-E-stabilizing peptide, which has previously shown the capacity to enhance adaptive NK cell response. The obtained K562-21E cell line was employed to investigate proliferative responses of the CD57− NK cell subset of HCMV-seropositive and seronegative donors. Stimulation of CD57− NK cells with K562-21E/peptide resulted in an increased cell expansion during the 12-day culturing period, regardless of the serological HCMV status of the donor. The enhanced proliferation in response to the peptide was associated with a greater proportion of CD56brightHLA-DR+ NK cells. In later stages of cultivation, the greatest proliferative response to K562-21E/peptide was shown for a highly HCMV-seropositive donor. These expanded NK cells were characterized by the accumulation of CD57−KIR2DL2/3+NKG2C+NKG2A− cells, which are hypothesized to represent adaptive NK cell progenitors. The K562-21E feeder cells can be applied both for the accumulation of NK cells as therapeutic effectors, and for the study of NK cell maturation into the adaptive state after the HLA-E peptide presentation.

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Section: Discussionmentioning

confidence: 99%

Obtaining Gene-Modified HLA-E-Expressing Feeder Cells for Stimulation of Natural Killer Cells

Alekseeva,

Streltsova,

Vavilova

et al. 2024

Pharmaceutics

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“…In this regard, NKG2C+ cells are a subset included in CD56dim CD16+ and CD56lo/-CD16+ NK cells initially identified as an expanded population in CMV infected individuals that is characterized by a primed state, including higher cytotoxic potential and enriched ADCC activity, and therefore, this subset has been considered to have memory-like properties (54,55). These cells originate from NKG2C-NKG2D+ precursors giving rise to immature NKG2C+ CD57-precursors and finally, mature NKG2C+ CD57+ memory cells (56)(57)(58)(59). In the case of HIV-1 infection, memory NKG2C+ NK cells have been shown to be capable of recognizing HLA-E expressing infected CD4+ T cells loaded with viral peptides (60,61).…”

Section: Introductionmentioning

confidence: 99%

Combined Dendritic Cell And Anti-TIGIT Immunotherapy Potentiate Trail+ Memory NK Cells Against HIV-1 Infected Cells

Sánchez-Cerrillo,

Popova,

Agudo-Lera

et al. 2024

Preprint

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Natural Killer (NK) cells are promising tools for the development of immunotherapies targeting persistently infected CD4+ T cells to potentially achieve remission in people with HIV-1 (PWH). However, the chronicity of HIV-1 infection limits the functional properties of NK cells, and additional approaches are needed to potentiate their cytotoxic activity against HIV-1-infected cells. In the present study, we analyzed the reinvigoration of functional NK cells from PWH after priming with autologous dendritic cells (DC) stimulated with nanoparticles containing Poly I:C (Nano-PIC). We show that improved natural cytotoxic function in NK cell from PWH associates with increased proportions of NKG2C+CD57- precursors of memory NK, which eliminate HIV-1 infected CD4+ T cells mainly through the TRAIL receptor. In addition, expression of TIGIT but not TIM3 limited increase in NKG2C+ memory NK cell precursors and associated with persistent dysfunctionality of NK cells after stimulation with Nano PIC-DC. Blockade of TIGIT restored functional capacities of NK cell from PWH eliminating HIV-1 infected cellsin vitro. Moreover, combining of NK cell and Nano-PIC-DC with anti-TIGIT mAbs immunotherapy limited the expansion of HIV-1 infected cells in humanized immunodeficient NSG mice transplanted with CD4+ T cells from PWHin vivo. Such viral control was associated with preserved NKG2C memory NK cell precursors, increased expression of granzyme B and TRAIL on NK in tissue from transplanted NSG mice. Together, combination of Nano-PIC DC and anti-TIGIT antibodies may be a promising strategy to increase the efficacy of immunotherapies aimed at HIV-1 cure.One sentence summaryStimulation of memory NK with a combination of DC and anti-TIGIT antibodies increase their ability to eliminate HIV-1 infected CD4+ T cellsin vitroandin vivo.

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“…Nevertheless, the precursors of adaptive NK cells with the CD57 -CD56 dim NKG2C + phenotype retain many properties of adaptive cells, while being highly proliferative [7]. It has been previously shown that NK cells with the CD57 -CD56 dim KIR + NKG2C + phenotype are able to respond with intense expansion to stimulation by IL-2 and K562-mbIL21 feeder cells [9]. To evaluate the stability of KIR2DL2/3 expression in the adaptive NK cell progenitor subpopulation, heterogeneous CD57 -CD56 dim cultures of KIR2DL2/3-positive subsets were obtained.…”

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confidence: 99%

NK cells expansion <i>in vitro</i> is followed by loss of inhibitory KIR expression

et al. 2023

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NK cells are innate lymphocytes that are able to eliminate altered cells, which makes them promising for the immunotherapy of viral diseases and tumors. The NK cell population is characterized by high phenotypic and functional diversity. In particular, in the pool of highly differentiated NK cells in the presence of cytomegalovirus (HCMV), a population of adaptive cells can be formed, characterized by a high lifespan and high cytotoxicity. However, in order to carry out a cytotoxic reaction, a NK cell must undergo a licensing process, during which it acquires the expression of NKG2A and KIRs. Currently, there are many effective methods of NK cell accumulation for subsequent use in therapy, one of them is the stimulation with IL-2 and K562-mbIL21 feeder cells. Highly differentiated adaptive-like NK cells are able to expand in respond to such stimulation. However, the phenotype of actively expanding NK cells dynamically changes. Loss of inhibitory KIR expression during intense proliferation of NK cells may adversely affect their cytotoxic potential. This work shows that highly differentiated CD56dimNKG2C+ NK cells from HCMV-seropositive individuals have a high proportion of KIR2DL2/3+ cells. This may indicate a high stability of KIR receptor expression in this population. We have shown that CD56dimNKG2C+ clonal cultures obtained by stimulation with IL-2 and K562- mbIL21 are characterized by high stability of KIR2DL2/3 expression compared to NKG2C-negative and less differentiated CD56brightNKG2C+. Also, in heterogeneous cultures of adaptive NK cells precursors CD57- CD56dimNKG2C+, a higher expression level of KIR2DL2/3 was observed in comparison with NKG2C-negative cultures of CD57-CD56dimNKG2C-. Thus, the accumulation of NK cells upon stimulation with IL-2 and K562- mbIL2 feeder cells can lead to loss of expression of KIR receptors and a decrease in their functional activity. However, cultures of highly differentiated NK cells of HCMV-seropositive individuals CD56dimNKG2C+, as well as cultures of precursors of adaptive NK cells CD57-CD56dimNKG2C+, are characterized by a greater stability of KIR2DL2/3 expression. As a result, stimulation with IL-2 and K562-mbIL21 feeder cells can be used to accumulate adaptive-like cells and their progenitors with stable inhibitory KIR expression and high cytotoxic potential.

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Increased Susceptibility of the CD57− NK Cells Expressing KIR2DL2/3 and NKG2C to iCasp9 Gene Retroviral Transduction and the Relationships with Proliferative Potential, Activation Degree, and Death Induction Response

Cited by 4 publications

References 44 publications

Obtaining Gene-Modified HLA-E-Expressing Feeder Cells for Stimulation of Natural Killer Cells

Obtaining Gene-Modified HLA-E-Expressing Feeder Cells for Stimulation of Natural Killer Cells

Combined Dendritic Cell And Anti-TIGIT Immunotherapy Potentiate Trail+ Memory NK Cells Against HIV-1 Infected Cells

NK cells expansion <i>in vitro</i> is followed by loss of inhibitory KIR expression

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