Human CD56dimCD16dim Cells As an Individualized Natural Killer Cell Subset

Amand, Mathieu; Iserentant, Gilles; Poli, Aurélie; Sleiman, Marwan; Fiévez, Virginie; Sánchez, Isaura Pilar; Sauvageot, Nicolas; Michel, Tatiana; Aouali, Nasséra; Janji, Bassam; Trujillo-Vargas, Claudia M.; Seguin-Devaux, Carole; Zimmer, Jacques

doi:10.3389/fimmu.2017.00699

Cited by 109 publications

(96 citation statements)

References 53 publications

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“…The V158F polymorphism of FcγRIIIA, which is associated with higher therapeutic response to RTX ( 31 – 33 ) or to the anti-ErB-2 mAb trastuzumab (TTZ) used in brain cancer ( 34 ), has also been related to interindividual variations in FcγRIIIA expression ( 35 , 36 ), although this is not confirmed ( 9 , 37 ). In the course of flow cytometry (FCM) analysis of human NK cells, we also noted a substantial intraindividual heterogeneity of FcγRIIIa expression on CD56 dim NK cells in accordance with a recent study, reporting the presence of an individualized subset of CD56 dim cells expressing low level of CD16 in human peripheral blood ( 38 ).…”

Section: Introductionsupporting

confidence: 90%

“…The differentiation/maturation of CD56 dim NK cells is associated with gain (KIRs and CD57) and loss (NKG2A and CD62L) of protein expression on the cell surface ( 21 – 26 ). On the one hand, Amand et al have recently described a new subset of CD56 dim NK cells with low level of FcγRIIIa ( 38 ). Phenotypically, the new subset contained a high percentage of relatively immature cells, as reflected by a significantly stronger representation of NKG2A + and CD57 − cells.…”

Section: Discussionmentioning

confidence: 99%

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Gradual Increase of FcγRIIIa/CD16a Expression and Shift toward IFN-γ Secretion during Differentiation of CD56dim Natural Killer Cells

et al. 2017

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Natural killer (NK) cell effector functions include cytotoxicity and secretion of cytokines such as interferon-γ (IFN-γ). The immature CD56bright subset of human NK cells lacks expression of FcγRIIIa/CD16a, one of the low-affinity immunoglobulin G receptors, or exhibits low-density expression (CD56brightCD16−/dim) and produces IFN-γ in response to cytokine stimulation, whereas the mature CD56dimCD16+ subset is the most cytotoxic one. A further differentiation/maturation of the latter subset according to the gradual loss of NKG2A and/or gain of KIR2DL (CD158a and CD158b) has been demonstrated and the ability to produce IFN-γ in response to activating receptor (AR) co-engagement is gradually acquired during terminal differentiation. In the course of flow cytometry analysis of CD56dim NK cells, we noted a substantial intraindividual heterogeneity of expression of FcγRIIIa. FcγRIIIa is unique among ARs: it does not require the co-engagement of other ARs to induce substantial cytotoxicity or cytokine synthesis in CD56dim cells. We, therefore, investigated whether individual differentiation/maturation of polyclonal CD56dim NK cells defined by expression of NKG2A/KIR2DL is related to FcγRIIIa expression and to the heterogeneity of NK cell responses upon FcγRIIIa engagement. When we analyzed unstimulated CD56dim cells by increasing level of FcγRIIIa expression, we found that the proportion of the more differentiated CD158a,h+ and/or CD158b,j+ cells and that of the less differentiated NKG2A+ cells gradually increased and decreased, respectively. FcγRIIIa engagement by using plate-bound murine anti-CD16 monoclonal antibody (mAb) or rituximab or trastuzumab (two therapeutic mAbs), resulted in donor-dependent partial segregation of IFN-γ-producing and/or degranulating CD56dim cells. Importantly, the proportion of CD158a,h/b,j+ cells and that of NKG2A+ cells was increased and decreased, respectively, IFN-γ-producing cells, whereas these proportions were poorly modified in degranulating cells. Similar results were observed after engagement of ARs by a combination of mAbs targeting NKG2D, NKp30, NKp46, and 2B4. Thus, the gradual increase of FcγRIIIa expression is an important feature of the differentiation/maturation of CD56dim cells and this differentiation/maturation is associated with a shift in functionality toward IFN-γ secretion observed upon both FcγRIIIa-dependent and FcγRIIIa-independent stimulation. The functional heterogeneity related to the differentiation/maturation of CD56dim NK cells could be involved in the variability of the clinical responses observed in patients treated with therapeutic mAbs.

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Section: Introductionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Gradual Increase of FcγRIIIa/CD16a Expression and Shift toward IFN-γ Secretion during Differentiation of CD56dim Natural Killer Cells

et al. 2017

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“…Changes in expression of NK cell receptors (NKRs) compared with those in healthy volunteers have been reported in viremic HIV-1 infection ( 27 , 28 ), but the HCMV serostatus of the subjects studied has not always been taken into consideration. We explored the diversity of NK cell phenotypes in a unique cohort of n = 21 HIV-1-infected male Caucasian individuals ( n = 20 HCMV-seropositive, n = 1 HCMV seronegative) recruited during acute infection and followed-up longitudinally both pre- and post-initiation of antiretroviral therapy, and compared with two groups of n = 10 HCMV-seropositive and n = 10 HCMV seronegative HIV-1 seronegative age matched male Caucasian controls (Tables S1 and S2 in Supplementary Material).…”

Section: Resultsmentioning

confidence: 99%

Adaptive Reconfiguration of Natural Killer Cells in HIV-1 Infection

et al. 2018

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Human cytomegalovirus (HCMV) co-infection is highly prevalent within HIV-1 cohorts and is an important cofactor in driving ongoing immune activation, even during effective antiretroviral treatment. HCMV infection has recently been associated with expansion of adaptive-like natural killer (NK) cells, which harbor epigenetic alterations that impact on their cellular function and phenotype. The influence of HCMV co-infection on the considerable heterogeneity among NK cells and their functional responses to different stimuli was assessed in a cohort of HIV-1-infected individuals sampled during different stages of infection, compared with healthy subjects stratified according to HCMV serostatus. Our data demonstrate a reshaping of the NK cell pool in HIV-1 infection of HCMV-seropositive individuals, with an accentuated peripheral transition of CD56dim NK cells toward a mature CD57+ CD85j+ NKG2C+ NKG2A− phenotype. Lack of PLZF further distinguishes adaptive NK cells from other NK cells expressing CD57 or NKG2C. PLZF− NK cells from HIV-infected individuals had high expression of CD2, were Siglec-7 negative and exhibited downregulation of key signaling molecules, SYK and FcεRI-γ, overwhelmingly displaying features of adaptive NK cells that correlated with HCMV serum Ab levels. Notably this adaptive-like signature was detected during early HIV-1 infection and persisted during treatment. Adaptive-like NK cell subsets in HIV-1-infected individuals displayed enhanced IFN-γ production following Fc receptor triggering compared with their conventional NK cell counterparts, and their ability to produce TNF-α and degranulate was preserved. Together, these data suggest that HMCV infection/reactivation, a hallmark of HIV-1 infection, plays a role in driving a relative expansion of NK cells with adaptive features during HIV-1 infection. The identification of selective NK subsets with retained effector activity in HIV-1-infected subjects raises the possibility of developing therapeutic strategies that exploit specific NK subpopulations to achieve better HIV-1 control.

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“…Within this NK cell subset, the cells with lower expression of CD16 (designated here as CD56 dim CD16 dim and shown in gate 4 in Supplementary Figure 1 panel B) were noted in CD patients relative to the cells in healthy controls. Interestingly, this NK cell subset was found to be depleted in HIV-infected and immunodeficient individuals [38]. The expansion of this subset in CD patients may have resulted from a decreased expression of CD16 on NK cells.…”

Section: Discussionmentioning

confidence: 98%

Phenotypic and Functional Changes in Peripheral Blood Natural Killer Cells in Crohn Disease Patients

Samarani

Sagala

Jantchou

et al. 2020

Mediators of Inflammation

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We investigated activation status, cytotoxic potential, and gut homing ability of the peripheral blood Natural Killer (NK) cells in Crohn disease (CD) patients. For this purpose, we compared the expression of different activating and inhibitory receptors (KIR and non-KIR) and integrins on NK cells as well as their recent degranulation history between the patients and age-matched healthy controls. The study was conducted using freshly obtained peripheral blood samples from the study participants. Multiple color flow cytometry was used for these determinations. Our results show that NK cells from treatment-naïve CD patients expressed higher levels of activating KIR as well as other non-KIR activating receptors vis-à-vis healthy controls. They also showed increased frequencies of the cells expressing these receptors. The expression of several KIR and non-KIR inhibitory receptors tended to decrease compared with the cells from healthy donors. NK cells from the patients also expressed increased levels of different gut-homing integrin molecules and showed a history of increased recent degranulation events both constitutively and in response to their in vitro stimulation. Furthermore, treatment of the patients tended to reverse these NK cell changes. Our results demonstrate unequivocally, for the first time, that peripheral blood NK cells in treatment-naïve CD patients are more activated and are more poised to migrate to the gut compared to their counterpart cells from healthy individuals. Moreover, they show that treatment of the patients tends to normalize their NK cells. The results suggest that NK cells are very likely to play a role in the immunopathogenesis of Crohn disease.

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Human CD56dimCD16dim Cells As an Individualized Natural Killer Cell Subset

Cited by 109 publications

References 53 publications

Gradual Increase of FcγRIIIa/CD16a Expression and Shift toward IFN-γ Secretion during Differentiation of CD56dim Natural Killer Cells

Gradual Increase of FcγRIIIa/CD16a Expression and Shift toward IFN-γ Secretion during Differentiation of CD56dim Natural Killer Cells

Adaptive Reconfiguration of Natural Killer Cells in HIV-1 Infection

Phenotypic and Functional Changes in Peripheral Blood Natural Killer Cells in Crohn Disease Patients

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