In contrast to anti-tumor activity, YT cell and primary NK cell cytotoxicity for Cryptococcus neoformans bypasses LFA-1

Jones, Gareth; Wiseman, John; Marr, Kaleb J.; Wei, Sheng; Djeu, Julie Y.; Mody, Christopher H.

doi:10.1093/intimm/dxp010

Cited by 21 publications

(20 citation statements)

References 56 publications

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“…Subsequently, the three cell types were incubated with YT cells to assess the protective role from overexpression of PI-9. It is worth noting that NK cells and the YT cell line undergo similar mechanisms of cytotoxicity (32), are stimulated by common surface Ags (33), and express similar surface markers (34). Therefore, both cell types are used interchangeably in the literature.…”

Section: Overexpression Of Pi-9 Protects Hpb-mscs From Killingmentioning

confidence: 99%

The Novel Role of SERPINB9 in Cytotoxic Protection of Human Mesenchymal Stem Cells

Haddad

Moore

Heathcote

et al. 2011

The Journal of Immunology

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Clinical trials using allogeneic mesenchymal stem cells (MSCs) are ongoing for the purpose of providing therapeutic benefit for a variety of human disorders. Pertinent to their clinical use are the accessibility to sufficient quantities of these cells allowing for repetitive administration, as well as a better understanding of the specific mechanisms by which allogeneic MSCs evade host immune responses that in turn influence their life span following administration. In this report, we sought to characterize and compare human peripheral blood MSCs (hPB-MSCs) with bone marrow-derived MSCs. hPB-MSCs met the established criteria to characterize this cellular lineage, including capacity for self-renewal, differentiation into tissues of mesodermal origin, and expression of phenotypic surface markers. In addition, hPB-MSCs suppressed alloreactive proliferation as well as the production of proinflammatory cytokines. Examination of the mechanisms by which allogeneic MSCs evade the host immune response, which is crucial for their therapeutic use, demonstrated that constitutive expression of serine protease inhibitor 9 (PI-9) on hPB-MSCs and bone marrow-derived MSCs is a major defense mechanism against granzyme B-mediated destruction by NK cells. Similarly, MSCs treated with small interfering RNA for PI-9 increased MSC cellular death, whereas expression of transgenic PI-9 following retroviral transduction protected MSCs. These data significantly advance our understanding of the immunomodulatory role for hPB-MSCs as well as the mechanisms by which they evade host immune responses. These findings contribute to the development of MSC-based therapies for diseases.

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Section: Overexpression Of Pi-9 Protects Hpb-mscs From Killingmentioning

confidence: 99%

The Novel Role of SERPINB9 in Cytotoxic Protection of Human Mesenchymal Stem Cells

Haddad

Moore

Heathcote

et al. 2011

The Journal of Immunology

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“…In contrast, NK cell contact with C. neoformans is not intimate but is characterized by NK cell microvilli penetrating the fungal capsule and binding to the underlying cell wall of the fungus. Maximal binding of NK cells to C. neoformans does not occur until after 2 h and is independent of LFA-1, and inhibition of fungal growth is not detectable until 4 h following maximal binding (14,23,43,44,46). With these similarities and differences in mind, we wondered whether NK cell microbicidal activity with C. neoformans is influenced in response to C. neoformans as it is in response to other target types.…”

mentioning

confidence: 99%

Cryptococcus neoformansDirectly Stimulates Perforin Production and Rearms NK Cells for Enhanced Anticryptococcal Microbicidal Activity

Marr¹,

Jones²,

Zheng

et al. 2009

Infect Immun

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NK cells, in addition to possessing antitumor and antiviral activity, exhibit perforin-dependent microbicidal activity against the opportunistic pathogen Cryptococcus neoformans. However, the factors controlling this response, particularly whether the pathogen itself provides an activation or rearming signal, are largely unknown. The current studies were performed to determine whether exposure to this fungus alters subsequent NK cell anticryptococcal activity. NK cells lost perforin and mobilized lysosome-associated membrane protein 1 to the cell surface following incubation with the fungus, indicating that degranulation had occurred. Despite a reduced perforin content during killing, NK cells acquired an enhanced ability to kill C. neoformans, as demonstrated using auxotrophs that allowed independent assessment of the killing of two strains. De novo protein synthesis was required for optimal killing; however, there was no evidence that a soluble factor contributed to the enhanced anticryptococcal activity. Exposure of NK cells to C. neoformans caused the cells to rearm, as demonstrated by increased perforin mRNA levels and enhanced loss of perforin when transcription was blocked. Degranulation alone was insufficient to provide the activation signal as NK cells lost anticryptococcal activity following treatment with strontium chloride. However, NK cells regained the activity upon prolonged exposure to C. neoformans, which is consistent with activation by the microbe. The enhanced cytotoxicity did not extend to tumor killing since NK cells exposed to C. neoformans failed to kill NK-sensitive tumor targets (K562 cells). These studies demonstrate that there is contact-mediated microbe-specific rearming and activation of microbicidal activity that are necessary for optimal killing of C. neoformans.

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“…To assess whether NK cells from HIV-infected patients were able to bind to C. neoformans , we labeled the NK cells with phycoerythrin (PE)-Cy5-conjugated anti-CD11a and then cocultured them with FITC-labeled C. neoformans over time. It is worth noting that direct NK cell anticryptococcal activity is preceded by LFA-1 (CD11a/CD18)-independent binding of NK cells (36). Conjugates were identified when red fluorescence (NK cell) and green fluorescence ( C. neoformans ) were detected in the same event by flow cytometry.…”

Section: Resultsmentioning

confidence: 99%

“…However, we considered the possibility that NK cells from HIV-infected patients failed to polarize perforin because they made contact but did not form a synapse with C. neoformans . To address this possibility, we examined LFA-1, which had been shown to accumulate at the NK cell-cryptococcal synapse (36). Images demonstrated that LFA-1 accumulates at the NK cell-cryptococcal synapse, in NK cells from both HIV-infected patients (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms by Which Interleukin-12 Corrects Defective NK Cell Anticryptococcal Activity in HIV-Infected Patients

Kyei

Ogbomo

et al. 2016

mBio

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Cryptococcus neoformans is a pathogenic yeast and a leading cause of life-threatening meningitis in AIDS patients. Natural killer (NK) cells are important immune effector cells that directly recognize and kill C. neoformans via a perforin-dependent cytotoxic mechanism. We previously showed that NK cells from HIV-infected patients have aberrant anticryptococcal killing and that interleukin-12 (IL-12) restores the activity at least partially through restoration of NKp30. However, the mechanisms causing this defect or how IL-12 restores the function was unknown. By examining the sequential steps in NK cell killing of Cryptococcus, we found that NK cells from HIV-infected patients had defective binding of NK cells to C. neoformans. Moreover, those NK cells that bound to C. neoformans failed to polarize perforin-containing granules to the microbial synapse compared to healthy controls, suggesting that binding was insufficient to restore a defect in perforin polarization. We also identified lower expression of intracellular perforin and defective perforin release from NK cells of HIV-infected patients in response to C. neoformans. Importantly, treatment of NK cells from HIV-infected patients with IL-12 reversed the multiple defects in binding, granule polarization, perforin content, and perforin release and restored anticryptococcal activity. Thus, there are multiple defects in the cytolytic machinery of NK cells from HIV-infected patients, which cumulatively result in defective NK cell anticryptococcal activity, and each of these defects can be reversed with IL-12.

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In contrast to anti-tumor activity, YT cell and primary NK cell cytotoxicity for Cryptococcus neoformans bypasses LFA-1

Cited by 21 publications

References 56 publications

The Novel Role of SERPINB9 in Cytotoxic Protection of Human Mesenchymal Stem Cells

The Novel Role of SERPINB9 in Cytotoxic Protection of Human Mesenchymal Stem Cells

Cryptococcus neoformansDirectly Stimulates Perforin Production and Rearms NK Cells for Enhanced Anticryptococcal Microbicidal Activity

Mechanisms by Which Interleukin-12 Corrects Defective NK Cell Anticryptococcal Activity in HIV-Infected Patients

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