Direct interactions of human lymphocytes with the yeast-like organism, Cryptococcus neoformans.

Murphy, Juneann W.; Hidore, M R; Wong, Si Chai

doi:10.1172/jci116361

Cited by 98 publications

(78 citation statements)

References 42 publications

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“…When the YT cells were separated from the C. neoformans, YT cells completely lost their anticryptococcal activity, suggesting that the YT cell-mediated antifungal activity is not due to soluble factors, but rather, it is contact dependent. This is consistent with previous studies that observed direct contact between human T cells, human NK cells, or mouse NK cells with C. neoformans by microscopic techniques (45)(46)(47)(48)(49). The importance of cell contact and the magnitude of the anticryptococcal activity are further emphasized by the observation that the growth of C. neoformans increased as the number of YT cells was increased on the other side of the membrane.…”

Section: Discussionsupporting

confidence: 91%

NK Cells Use Perforin Rather than Granulysin for Anticryptococcal Activity

Ling

Wang²,

Neely

et al. 2004

The Journal of Immunology

103

111

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Cytotoxic lymphocytes have the capacity to kill microbes directly; however, the mechanisms involved are poorly understood. Using Cryptococcus neoformans, which causes a potentially fatal fungal infection in HIV-infected patients, our previous studies showed that granulysin is necessary, while perforin is dispensable, for CD8 T lymphocyte fungal killing. By contrast, the mechanisms by which NK cells exert their antimicrobial activity are not clear, and in particular, the contribution of granulysin and perforin to NK-mediated antifungal activity is unknown. Primary human NK cells and a human NK cell line YT were found to constitutively express granulysin and perforin, and possessed anticryptococcal activity, in contrast to CD8 T lymphocytes, which required stimulation. When granulysin protein and mRNA were blocked by granulysin small interfering RNA, the NK cell-mediated antifungal effect was not affected in contrast to the abrogated activity observed in CD8 T lymphocytes. However, when perforin was inhibited by concanamycin A, and silenced using hairpin small interfering RNA, the anticryptococcal activities of NK cells were abrogated. Furthermore, when granulysin and perforin were both inhibited, the anticryptococcal activities of the NK cells were not reduced further than by silencing perforin alone. These results indicate that the antifungal activity is constitutively expressed in NK cells in contrast to CD8 T lymphocytes, in which it requires prior activation, and perforin, but not granulysin, plays the dominant role in NK cell anticryptococcal activity, in contrast to CD8 T lymphocytes, in which granulysin, but not perforin, plays the dominant role in anticryptococcal activity.

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Section: Discussionsupporting

confidence: 91%

NK Cells Use Perforin Rather than Granulysin for Anticryptococcal Activity

Ling

Wang²,

Neely

et al. 2004

The Journal of Immunology

103

111

View full text Add to dashboard Cite

show abstract

“…This is supported by the observation that perforin acts as a gateway for granzymes through the plasma membrane. Both of these events might require intimate contact of the T lymphocyte and the target, and previous studies have shown that intimate contact between the T lymphocytes and C. neoformans is required for the anticryptococcal activities (23,46,67). Thus, it may be that perforin is required for granulysin to access the compartment containing mycobacteria, but granulysin is directly active on extracellular C. neoformans at the conjugation region.…”

Section: Discussionmentioning

confidence: 99%

CD8 T Cell-Mediated Killing ofCryptococcus neoformansRequires Granulysin and Is Dependent on CD4 T Cells and IL-15

Ling

Spurrell

Wang

et al. 2002

The Journal of Immunology

131

108

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Granulysin is located in the acidic granules of cytotoxic T cells. Although the purified protein has antimicrobial activity against a broad spectrum of microbial pathogens, direct evidence for granulysin-mediated cytotoxicity has heretofore been lacking. Studies were performed to examine the regulation and activity of granulysin expressed by CD8 T cells using Cryptococcus neoformans, which is one of the most common opportunistic pathogens of AIDS patients. IL-15-activated CD8 T cells acquired anticryptococcal activity, which correlated with the up-regulation of granulysin. When granules containing granulysin were depleted using SrCl2, or when the gene was silenced using 21-nt small interfering RNA duplexes, the antifungal effect of CD8 T cells was abrogated. Concanamycin A and EGTA did not affect the antifungal effect, suggesting that the activity of granulysin was perforin independent. Following stimulation by the C. neoformans mitogen, CD8 T cells expressed granulysin and acquired antifungal activity. This activity required CD4 T cells and was dependent upon accessory cells. Furthermore, IL-15 was both necessary and sufficient for granulysin up-regulation in CD8 T cells. These observations are most consistent with a mechanism whereby C. neoformans mitogen is presented to CD4 T cells, which in turn activate accessory cells. The resultant IL-15 activates CD8 T cells to express granulysin, which is responsible for antifungal activity.

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“…However, C. neoformans is a fungal pathogen that primarily afflicts immunocompromised subjects such as those affected by HIV, where the cellmediated immune response (T and NK) is significantly impaired. In these patients, phagocytosis might not represent an effective mechanism of defense by the host, when the activation of T and/or NK cells and, thus, the production of activated macrophages are significantly reduced (6,(47)(48)(49). Moreover, in the case of facultative intracellular pathogens, such as C. neoformans, for which intracellular growth can be a favorable condition, phagocytosis may represent a successful strategy for better survival in the host.…”

Section: Discussionmentioning

confidence: 99%

Identification of App1 as a regulator of phagocytosis and virulence of Cryptococcus neoformans

Luberto¹,

Martinez-Mariño²,

Taraskiewicz³

et al. 2003

J. Clin. Invest.

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Cryptococcus neoformans is a fungal pathogen that, after inhalation, can disseminate to the brain. Host alveolar macrophages (AMs) represent the first defense against the fungus. Once phagocytosed by AMs, fungal cells are killed by a concerted mechanism, involving the host-cellular response. If the cellular response is impaired, phagocytosis of the fungus may be detrimental for the host, since C. neoformans can grow within macrophages. Here, we identified a novel cryptococcal gene encoding antiphagocytic protein 1 (App1). App1 is a cryptococcal cytoplasmic protein that is secreted extracellularly and found in the serum of infected patients. App1 does not affect melanin production, capsule formation, or growth of C. neoformans. Treatment with recombinant App1 inhibited phagocytosis of fungal cells through a complement-mediated mechanism, and Δapp1 mutant is readily phagocytosed by AMs. Interestingly, the Δapp1 mutant strain showed a decreased virulence in mice deficient for complement C5 (A/Jcr), but it was hypervirulent in mice deficient for T and NK cells (Tgε26). This study identifies App1 as a novel regulator of virulence for C. neoformans, and it highlights that internalization of fungal cells by AMs increases the dissemination of C. neoformans when the host cellular response is impaired

show abstract

Direct interactions of human lymphocytes with the yeast-like organism, Cryptococcus neoformans.

Cited by 98 publications

References 42 publications

NK Cells Use Perforin Rather than Granulysin for Anticryptococcal Activity

NK Cells Use Perforin Rather than Granulysin for Anticryptococcal Activity

CD8 T Cell-Mediated Killing ofCryptococcus neoformansRequires Granulysin and Is Dependent on CD4 T Cells and IL-15

Identification of App1 as a regulator of phagocytosis and virulence of Cryptococcus neoformans

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