CD16 cross-linking induces increased expression of CD56 and production of IL-12 in peripheral NK cells

Marquez, Maria-Elena; Millet, Carmen; Stekman, Hilda; Conesa, Angela; Deglesne, Pierre-Antoine; Toro, Félix; Sanctis, Juan De; Blanca, Isaac

doi:10.1016/j.cellimm.2010.05.002

Cited by 21 publications

(20 citation statements)

References 31 publications

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“…In addition to killing infected cells, this process could liberate granulysin, present in cytotoxic granules, which works as an alarmin and activates DCs [39]. Besides this degranulation activity, through binding of CD16, NK cells are able to activate adaptive immune responses by the secretion of soluble factors such as IFN-g and TNF-a [40]. We showed that VLP stimulation induced the secretion of these cytokines in NK and NK92 CD16…”

Section: Discussionmentioning

confidence: 86%

Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion

et al. 2011

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Human papillomavirus (HPV) infections account for more than 50% of infection-linked cancers in women worldwide. The immune system controls, at least partially, viral infection and around 90% of HPV-infected women clear the virus within two years. However, it remains unclear which immune cells are implicated in this process and no study has evaluated the direct interaction between HPVs and NK cells, a key player in host resistance to viruses and tumors. We demonstrated an NK-cell infiltration in HPVassociated preneoplastic cervical lesions. Since HPVs cannot grow in vitro, virus-like particles (VLPs) were used as a model for studying the NK-cell response against the virus. Interestingly, NK cells displayed higher cytotoxic activity and cytokine production (TNF-a and IFN-c) in the presence of HPV-VLPs. Using flow cytometry and microscopy, we observed that NK-cell stimulation was linked to rapid VLP entry into these cells by macropinocytosis. Using CD16 1 and CD16 À NK-cell lines and a CD16-blocking antibody, we demonstrated that CD16 is necessary for HPV-VLP internalization, as well as for degranulation and cytokine production. Thus, we show for the first time that NK cells interact with HPVs and can participate in the immune response against HPV-induced lesions. IntroductionHigh-risk human papillomaviruses (HPVs) are the causative agents of uterine cervical cancer and are also etiologically associated with other anogenital tumors and with head and neck carcinomas [1].Among the 100 HPV genotypes already characterized, 15 are oncogenic and more than 50% of uterine cervical cancers are associated with HPV16 [2]. Because of their keratinocyte differentiation-dependent life cycle, virus production in vitro has required complex cell culture systems and only low virus titers can be obtained [3]. Consequently, most studies aiming to investigate interactions between virus and host cells have used virus-like particles (VLPs), which result from HPV L1 major capsid protein self-assembly and which are morphologically and immunologically [5,6]. Yet, these vaccines have no therapeutic efficacy and it has been estimated that there will be no measurable decline of HPVassociated tumors before 2040 [7].HPV infection can be controlled by the host immune response and the vast majority of HPV-infected women clear the virus within two years [8]. Moreover, the prevalence of HPV-induced tumors is higher in immunodeficient patients [9]. However, it remains unclear which immune cells are implicated in this process and no study has been performed evaluating the direct interaction between HPVs and NK cells, although these cells play a key role in host resistance to viruses [10] (Fig. 1A and B), but not in squamous cell carcinoma (SCC) (Fig. 1D) despite the presence of more numerous NK cells in the surrounding stroma (Supporting Information Fig. 1). Interestingly, virus particles have been detected mainly in SILs and not in SCC [19] where the virus is usually integrated into the host genome [20]. Our results thus suggest that NK cells could...

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Section: Discussionmentioning

confidence: 86%

Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion

et al. 2011

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“…The disadvantages of these methods are higher cost, more complicated procedures and requiring specialized processing equipments. CD16 engagement triggers potent NK cell activation and cytotoxicity against target cells [26, 44]. IL-2 is one of the key cytokines for induction of NK cell development, activation, proliferation and survival [45].…”

Section: Discussionmentioning

confidence: 99%

“…CD16 is one type of Fcγ receptors, a low-affinity receptor (FcγRIIIa) for the Fc portion of immunoglobulin, and cross-linking of CD16 to target cells induces NK cell antibody-dependent cellular cytotoxicity (ADCC) and lysis of the target cells [25]. Binding of CD16 agonist anti-CD16 antibody on NK cells is capable of triggering NK cell activation that results in NK cell cytotoxic activity against cancer cells and releasing of cytokines, such as interferon γ (IFNγ) [25, 26]. Moreover, blocking CD16 cleavage by inhibiting ADAM metallopeptidase domain 17 (ADAM17) to boost NK cell cytotoxicity towards cancers has been suggested by a recent study [27].…”

Section: Introductionmentioning

confidence: 99%

PD1 blockade enhances cytotoxicity of in vitro expanded natural killer cells towards myeloma cells

et al. 2016

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Aiming for an adoptive natural killer (NK) cell therapy, we have developed a novel protocol to expand NK cells from peripheral blood. With this protocol using anti-human CD16 antibody and interleukin (IL)-2, NK (CD3−CD56+) cells could be expanded about 4000-fold with over 70% purity during a 21-day culture. The expanded NK (exNK) cells were shown to be highly cytotoxic to multiple myeloma (MM) cells (RPMI8226) at low NK-target cell ratios. Furthermore, NK cells expanded in the presence of a blocking antibody (exNK+PD1-blockage) against programmed cell death protein-1 (PD1), a key counteracting molecule for NK and T cell activity, demonstrated more potent cytolytic activity against the RPMI8226 than the exNK cells without PD1 blocking. In parallel, the exNK cells showed significantly higher expression of NK activation receptors NKG2D, NKp44 and NKp30. In a murine model of MM, transfusion of exNK cells, exNK+PD1-blockage, and exNK plus intratumor injection of anti-PD-L2 antibody (exNK+PD-L2 blockage) all significantly suppressed tumor growth and prolonged survival of the myeloma mice. Importantly, exNK+PD1-blockage presented more efficient therapeutic effects. Our results suggest that the NK cell expansion protocol with PD1 blockade presented in this study has considerable potential for the clinical application of allo- and auto-NK cell-based therapies against malignancies.

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“…Therefore, an increase in CD16 is associated with an increased activation status and capacity to perform ADCC functions. Studies indicate that CD16/ligand cross-linking also leads to increases in additional activation markers (e.g., CD69) (Marquez et al, 2010). In addition to CD16, CD69 is one of the earliest markers expressed on the cell surface of activated NK cells.…”

Section: Discussionmentioning

confidence: 99%

“…CD69 acts as a costimulatory receptor that leads to cytotoxicity, cell proliferation, and/or cytokine secretion (Borrego et al, 1999). The relationship between CD16 and CD69 upregulation is a strong and important one where evidence suggests that both receptors have the capacity to activate NK cytotoxic and anti-viral cytokine mechanisms (Marquez et al, 2010; Moretta et al, 1991). The current experiments indicate that SDR significantly increased both CD16 and CD69 surface expression on splenic CD3-/DX5+ NK cells.…”

Section: Discussionmentioning

confidence: 99%

β-Adrenergic receptor mediated increases in activation and function of natural killer cells following repeated social disruption

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et al. 2012

Brain, Behavior, and Immunity

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CD16 cross-linking induces increased expression of CD56 and production of IL-12 in peripheral NK cells

Cited by 21 publications

References 31 publications

Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion

Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion

PD1 blockade enhances cytotoxicity of in vitro expanded natural killer cells towards myeloma cells

β-Adrenergic receptor mediated increases in activation and function of natural killer cells following repeated social disruption

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