Interleukin-18 Synergism with Interleukin-2 in Cytotoxicity and NKG2D Expression of Human Natural Killer Cells

Qi, Yuanying; Lü, Chao; Ju, Ying; Wang, Zie; Li, Yuan-Tang; Shen, Yajuan; Lu, Zhiming

doi:10.7314/apjcp.2014.15.18.7857

Cited by 3 publications

(2 citation statements)

References 31 publications

(37 reference statements)

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“…These include death receptors that are members of the TNF receptor gene superfamily such as FasL/FasR, TNF-α/ TNFR1, Apo3L/DR3, Apo2L/DR4 and Apo2L/DR5 (Locksley et al, 2001;Rubio-Moscardo et al, 2005). Fourth is an indirect mechanism that depends on myeloid accessory cells that respond to pattern recognition receptors (PRR) by production of cytokines such as IL-2, IL-12, IL-15, IL-18 or IFN-γ (Horowitz et al, 2012;Qi et al, 2014;Fauriat et al, 2013). Particularly, the CD-56 bright subpopulation which constitutively expresses the high affinity IL-2 receptor (IL-2R, CD25) can be driven to activation and proliferate in response to IL-2 and IL-15 (Baume et al, 2012;Carson et al, 2007;Bachmann & Oxenius, 2007).…”

Section: Introductionmentioning

confidence: 99%

CD25 (IL-2R) expression correlates with the target cell induced cytotoxic activity and cytokine secretion in human natural killer cells

2015

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Cytotoxic activity is one of the major functions of Natural Killer (NK) cells and is a critical effector mechanism of innate immune responses against infected or cancer cells. A variety of assays have been developed to determine NK cell cytotoxic activity, however a receptor-based screening tool is still lacking. Here, we propose the CD25 receptor as a candidate for NK cell cytotoxicity marker. We have verified that there is a correlation between classic target cell induced cytotoxicity markers and the CD25 expression on NK cells. Non-adherent lymphocyte fractions pre-stimulated with Escherichia coli O55:B5 lipopolysaccharide were co-cultured with settled HeLa targets in a four hour long cytotoxic assay. The cytotoxic effect was evaluated by MTT reduction assay and quantification of soluble cytotoxicity markers (granzyme B, FasL, caspase-8, IFN-γ and IL-2) was done by ELISA. Lymphocytes were stained with anti-CD3-Cy-5, anti-CD56/CD16/Nkp46-FITC and anti-CD25-PE antibodies and analyzed by flow cytometry. We observed that the CD25 expression exclusively on the CD3(-)CD56(+)CD25(+) NK cells was positively correlated with their cytotoxic function evaluated by the MTT test (r = 0.68), the upregulation of granzyme B (r = 0.89), IL-2 (r = 0.78) and IFN-γ (r = 0.57), however, it was not positively correlated with FasL and caspase-8. We conclude that the CD25 expression might serve as an in vitro receptor-based screening tool for NK cell activity.

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Section: Introductionmentioning

confidence: 99%

CD25 (IL-2R) expression correlates with the target cell induced cytotoxic activity and cytokine secretion in human natural killer cells

2015

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“…NKG2D and TNF-a up-regulation was due to elevated pSTAT5 IL-2 was reported to promote the expression of NKG2D [40,41] and TNF-a [42,43] and was the only cytokine added in the duration of cell expansion and rapamycin treatment. Besides, STAT5 activation was also reported to promote TNF-a [44,45] and NKG2D (see Supplemental data in ref.…”

Section: The Blocking Of Nkg2d and Tnf-a Suppressed Cytotoxicity Of Rmentioning

confidence: 99%

mTOR inhibition potentiates cytotoxicity of Vγ4 γδ T cells via up-regulating NKG2D and TNF-α

Cao

Wang

et al. 2016

Journal of Leukocyte Biology

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γδ T cells play a critical role in early anti-tumor immunity and perform cytotoxicity via NKG2D for recognition and multiple cytotoxic factors for tumor killing. Recent studies have demonstrated pivotal roles of mTOR-mediated metabolism in the maturation, differentiation, and effector function of diverse immune cells, including DCs, NK cells, CD4 T cell subsets, and CD8 T cells, but the role of mTOR signaling in γδ T cells is barely known. Here, we showed that suppressing mTOR signaling in in vitro-expanded Vγ4 γδ T cells via the mechanistic inhibitor rapamycin enhanced their cytotoxicity against multiple tumor cell lines, and these cells performed better tumor-suppressing effects upon adoptive therapy. Further investigation revealed that elevated cytotoxicity was a result of up-regulation of NKG2D and TNF-α. Moreover, rapamycin treatment significantly decreased the expression of CISH and increased pSTAT5. The inhibition of STAT5 pathways via siRNA interference or a specific inhibitor eliminated the up-regulation of NKG2D and TNF-α in rapamycin-treated Vγ4 γδ T cells. These results uncovered an important role of mTOR signaling in the cytotoxic effector function of γδ T cells and provided a potential strategy to improve γδ T cell-based cancer immunotherapy.

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Effector memory CD8 T cell response elicits Hepatitis E Virus genotype 3 pathogenesis in the elderly

et al. 2021

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Genotype 3 Hepatitis E virus (HEV-3) is an emerging threat for aging population. More than one third of older infected patients develops clinical symptoms with severe liver damage, while others remain asymptomatic. The origin of this discrepancy is still elusive although HEV-3 pathogenesis appears to be immune-mediated. Therefore, we investigated the role of CD8 T cells in the outcome of the infection in immunocompetent elderly subjects. We enrolled twenty two HEV-3-infected patients displaying similar viral determinants and fifteen healthy donors. Among the infected group, sixteen patients experienced clinical symptoms related to liver disease while six remained asymptomatic. Here we report that symptomatic infection is characterized by an expansion of highly activated effector memory CD8 T (EM) cells, regardless of antigen specificity. This robust activation is associated with key features of early T cell exhaustion including a loss in polyfunctional type-1 cytokine production and partial commitment to type-2 cells. In addition, we show that bystander activation of EM cells seems to be dependent on the inflammatory cytokines IL-15 and IL-18, and is supported by an upregulation of the activating receptor NKG2D and an exuberant expression of T-Bet and T-Bet-regulated genes including granzyme B and CXCR3. We also show that the inflammatory chemokines CXCL9-10 are increased in symptomatic patients thereby fostering the recruitment of highly cytotoxic EM cells into the liver in a CXCR3-dependent manner. Finally, we find that the EM-biased immune response returns to homeostasis following viral clearance and disease resolution, further linking the EM cells response to viral burden. Conversely, asymptomatic patients are endowed with low-to-moderate EM cell response. In summary, our findings define immune correlates that contribute to HEV-3 pathogenesis and emphasize the central role of EM cells in governing the outcome of the infection.

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Interleukin-18 Synergism with Interleukin-2 in Cytotoxicity and NKG2D Expression of Human Natural Killer Cells

Cited by 3 publications

References 31 publications

CD25 (IL-2R) expression correlates with the target cell induced cytotoxic activity and cytokine secretion in human natural killer cells

CD25 (IL-2R) expression correlates with the target cell induced cytotoxic activity and cytokine secretion in human natural killer cells

mTOR inhibition potentiates cytotoxicity of Vγ4 γδ T cells via up-regulating NKG2D and TNF-α

Effector memory CD8 T cell response elicits Hepatitis E Virus genotype 3 pathogenesis in the elderly

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