Mechanisms of NK cell activation: CD4+ T cells enter the scene

Bihl, Franck; Germain, Claire; Luci, Carmelo; Braud, Véronique M.

doi:10.1007/s00018-011-0796-1

Cited by 36 publications

(31 citation statements)

References 178 publications

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“…Experimental procedures aiming at the study of NK cells usually either involve the depletion of NK cells using monoclonal antibodies, like anti-NK1.1 or anti-asialo-GM1, both of which are not NK-cell-specific but deplete also subsets of T cells, or the use of immune-deficient mice, like Rag2 −/− γc −/− mice that lack not only NK cells, but also other ILC lineages as well as B and T cells, and display defects in lymphoid tissues, like lymph nodes and Peyer's patches [44]. Moreover, recent reports have underscored the importance of the reciprocal cross-talk between NK cells and other innate and adaptive immune cells for regulating immune responses [9,10]. Thus, it would appear important to preserve an intact environment when assessing the roles for NK cells in immune responses.…”

Section: Discussionmentioning

confidence: 99%

“…Given that the activity and differentiation of NK cells is intimately regulated by other immune cells (reviewed in [9,10]), the consequences of gene deletions that intrinsically affect NK cells may be difficult to distinguish from indirect effects that occur in non-NK cells. Furthermore, studying the role of NK cells in immune responses often involves the use of genetargeted mice lacking NK cells that also harbor other lymphoid defects (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Conditional ablation of NKp46⁺ cells using a novel Ncr1^greenCre mouse strain: NK cells are essential for protection against pulmonary B16 metastases

et al. 2014

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To study gene functions specifically in NKp46 + cells we developed novel Cre mice allowing for conditional gene targeting in cells expressing Ncr1 (encoding NKp46). We generated transgenic Ncr1 greenCre mice carrying an EGFPcre fusion under the control of a proximal Ncr1 promoter that faithfully directed EGFPcre expression to NKp46 + cells from lymphoid and nonlymphoid tissues. This approach allowed for direct detection of Cre-expressing NKp46 + cells via their GFP signature by flow cytometry and histology. Cre was functional as evidenced by the NKp46 + cell-specific expression of RFP in Ncr1 greenCre RosadtRFP reporter mice. We generated Ncr1 greenCre Il2rg fl/fl mice that lack NKp46 + cells in an otherwise intact hematopoietic environment. Il2rg encodes the common gamma chain (γ c ), which is an essential receptor subunit for cytokines (IL-2, -4, -7, -9, -15, and -21) that stimulate lymphocyte development and function. In Ncr1 greenCre Il2rg fl/fl mice, NK cells are severely reduced and the few remaining NKp46 + cells escaping γc deletion failed to express GFP. Using this new NK-cell-deficient model, we demonstrate that the homeostasis of NKp46 + cells from all tissues (including the recently described intraepithelial ILC1 subset) requires Il2rg. Eur. J. Immunol. 2014. 44: 3380-3391 Innate immunity 3381 in vivo and their capacity to promptly kill target cells (including tumors and infected cells) without prior sensitization [1][2][3]. NK cells have been shown to participate in immune responses to various microbial pathogens, including viruses, bacteria, and parasites (reviewed in [4]) through secretion of type 1 cytokines that recruit and activate hematopoietic effector cells. In the mouse, NK cells can be identified as CD3-NKp46 + cells that coexpress NK1.1 on appropriate genetic backgrounds (including C57BL/6). NK cells do not represent a homogeneous cell population but can be phenotypically separated into several subpopulations. Commonly used cell surface markers include CD27 and CD11b that divide NK-cell populations into CD27 + CD11b − NK cells (representing the least differentiated cells) that give rise to CD27 − CD11b + NK cells via CD27 + CD11b + NK-cell intermediates [5,6]. CD11b + NK cells can be further subdivided on the basis of KLRG1 expression with KLRG1 + marking terminally differentiated NK cells [7]. NK cells have been detected in lymphoid tissues, including bone marrow (BM), spleen, lymph nodes (LNs), Peyer's patches, and thymus, but also in nonlymphoid tissues, including liver, lungs, uterus, pancreas, skin, and intestine (reviewed in [8]).Many studies aiming at deciphering gene functions for NK cells make use of germ-line gene targeted mice where all cells lack the gene in question. Given that the activity and differentiation of NK cells is intimately regulated by other immune cells (reviewed in [9,10]), the consequences of gene deletions that intrinsically affect NK cells may be difficult to distinguish from indirect effects that occur in non-NK cells. Furthermore, studying the role of N...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Conditional ablation of NKp46⁺ cells using a novel Ncr1^greenCre mouse strain: NK cells are essential for protection against pulmonary B16 metastases

et al. 2014

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“…These data suggest that the distribution of this polymorphism is very similar in different Chinese populations. IL-2 is a potent inducer for T cell proliferation as well as Th1 and Th2 differentiation, and it provides T cells with a long-lasting competitive advantage resulting in the optimal survival and function of memory cells [7][8][9]. More and more evidence have implied that IL-2 may act as one of the key factors for CAD.…”

Section: Discussionmentioning

confidence: 97%

“…In addition to its effects on CD4 and CD8 T cells, IL-2 also stimulates natural killer cells to proliferate and induces cytolytic activity when present at high levels and stimulates B cells to divide and produce antibody [9]. The phenotype of IL-2-and CD25-deficient mice has led to an appreciation of the importance of IL-2 in controlling immune responses [7,8].…”

Section: Introductionmentioning

confidence: 98%

Effect of Interleukin-2 Level and Genetic Variants on Coronary Artery Disease

et al. 2013

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Inflammation plays important roles in the development of atherosclerosis and coronary artery disease (CAD). Interleukin-2 (IL-2) is a proinflammatory cytokine and induces proliferation of T cells. The aim of the study was to understand the effect of IL-2 on the development of CAD from genetic polymorphism perspective and serum level perspective. IL-2 -330T/G and +114T/G polymorphisms were tested in 692 CAD cases and 723 healthy controls. IL-2 expression of these two polymorphisms was compared. Serum level of IL-2 in CAD patients and controls was analyzed. Data showed that prevalence of IL-2 -330GG genotype was significantly increased in CAD than in controls (p = 5.1 × 10(-6)). Function analysis revealed that subjects carrying IL-2 -330GG genotype had higher serum level of IL-2 than those with TG or TT genotypes (p < 0.01). Serum level of IL-2 in the study subjects was further analyzed, and results showed that CAD patients had significantly increased IL-2 level than healthy controls (p < 0.01). Also, cases with three vessels affected were observed to have higher IL-2 level than cases with one vessel affected (p < 0.05). These data suggested IL-2 polymorphism could affect the susceptibility to CAD by elevating protein expression, and serum level of IL-2 may be closed correlated with the development and progression of this disease.

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“…Complex intercellular interactions in such multi-cellular clusters may synergize and coordinate immune responses, but at the same time, immune cells may also compete with each other for the limited supply of cytokines. For example, CD4 + T cells, CD8 + T cells, regulatory T cells (Tregs), and NK cells all require IL-2 for their activation and proliferation, but Tregs, which constitutively express high-affinity IL-2 receptors (IL-2Rs), consume large amounts of IL-2 to limit the accessible amounts of IL-212131415. Formation of multi-cellular clusters can not only promote interactions among different cell types, but also increase the probability of interactions among identical cells, or homotypic cell-to-cell interactions1617.…”

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confidence: 99%

Multi-cellular natural killer (NK) cell clusters enhance NK cell activation through localizing IL-2 within the cluster

Kim

et al. 2017

Sci Rep

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Multi-cellular cluster formation of natural killer (NK) cells occurs during in vivo priming and potentiates their activation to IL-2. However, the precise mechanism underlying this synergy within NK cell clusters remains unclear. We employed lymphocyte-laden microwell technologies to modulate contact-mediated multi-cellular interactions among activating NK cells and to quantitatively assess the molecular events occurring in multi-cellular clusters of NK cells. NK cells in social microwells, which allow cell-to-cell contact, exhibited significantly higher levels of IL-2 receptor (IL-2R) signaling compared with those in lonesome microwells, which prevent intercellular contact. Further, CD25, an IL-2R α chain, and lytic granules of NK cells in social microwells were polarized toward MTOC. Live cell imaging of lytic granules revealed their dynamic and prolonged polarization toward neighboring NK cells without degranulation. These results suggest that IL-2 bound on CD25 of one NK cells triggered IL-2 signaling of neighboring NK cells. These results were further corroborated by findings that CD25-KO NK cells exhibited lower proliferation than WT NK cells, and when mixed with WT NK cells, underwent significantly higher level of proliferation. These data highlights the existence of IL-2 trans-presentation between NK cells in the local microenvironment where the availability of IL-2 is limited.

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Mechanisms of NK cell activation: CD4+ T cells enter the scene

Cited by 36 publications

References 178 publications

Conditional ablation of NKp46⁺ cells using a novel Ncr1^greenCre mouse strain: NK cells are essential for protection against pulmonary B16 metastases

Conditional ablation of NKp46⁺ cells using a novel Ncr1^greenCre mouse strain: NK cells are essential for protection against pulmonary B16 metastases

Effect of Interleukin-2 Level and Genetic Variants on Coronary Artery Disease

Multi-cellular natural killer (NK) cell clusters enhance NK cell activation through localizing IL-2 within the cluster

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Mechanisms of NK cell activation: CD4+ T cells enter the scene

Cited by 36 publications

References 178 publications

Conditional ablation of NKp46+ cells using a novel Ncr1greenCre mouse strain: NK cells are essential for protection against pulmonary B16 metastases

Conditional ablation of NKp46+ cells using a novel Ncr1greenCre mouse strain: NK cells are essential for protection against pulmonary B16 metastases

Effect of Interleukin-2 Level and Genetic Variants on Coronary Artery Disease

Multi-cellular natural killer (NK) cell clusters enhance NK cell activation through localizing IL-2 within the cluster

Contact Info

Product

Resources

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Conditional ablation of NKp46⁺ cells using a novel Ncr1^greenCre mouse strain: NK cells are essential for protection against pulmonary B16 metastases

Conditional ablation of NKp46⁺ cells using a novel Ncr1^greenCre mouse strain: NK cells are essential for protection against pulmonary B16 metastases