Phenotypic and functional characterization of human lymphocytes activated by interleukin-2 to directly inhibit growth of Cryptococcus neoformans in vitro.

Levitz, S M; Dupont, Maxime

doi:10.1172/jci116354

Cited by 82 publications

(88 citation statements)

References 36 publications

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“…Nevertheless, the inability of IgG1 to confer protection in the SCID, CD4 Ϫ/Ϫ , and IFN-␥-deficient mice, and the restitution of IgG1-mediated protection when IFN-␥ was administered to the CD4 Ϫ/Ϫ mice, focuses attention on Th1 T cells and their role in activating macrophages and other effector cells. Other cytokines such as interleukins 2, 10, 12, and 13; transforming growth factor ␤; and granulocyte͞macrophage colonystimulating factor play important roles in regulating the activation of immune effector cells in cryptococcal infection (40)(41)(42). Nevertheless, IFN-␥ alone administered at the beginning of the infection was sufficient to produce antibodymediated protection in this model of infection.…”

Section: Discussionmentioning

confidence: 99%

T cells cooperate with passive antibody to modifyCryptococcus neoformansinfection in mice

Yuan

Casadevall

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

146

115

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Section: Discussionmentioning

confidence: 99%

T cells cooperate with passive antibody to modifyCryptococcus neoformansinfection in mice

Yuan

Casadevall

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

146

115

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“…The organisms were maintained on Sabouraud dextrose slants (Difco) and passaged to fresh slants every month as previously described (21). CFU were determined as previously described (22)(23)(24). C. neoformans (2 ϫ …”

Section: Semiquantitative Rt-pcrmentioning

confidence: 99%

Late Expression of Granulysin by Microbicidal CD4+ T Cells Requires PI3K- and STAT5-Dependent Expression of IL-2Rβ That Is Defective in HIV-Infected Patients

Zheng

Jones²,

Shi³

et al. 2008

The Journal of Immunology

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Granulysin is a cytolytic effector molecule used by lymphocytes to kill tumor and microbial cells. Regulation of granulysin production is complex. A significant delay (5 days) following stimulation of CD4+ T cells with IL-2 occurs before granulysin is produced. Unfortunately, the mechanisms responsible for this delay are unknown. We have recently demonstrated that granulysin-mediated killing of Cryptococcus neoformans by CD4+ T cells is defective during HIV infection. This is because CD4+ T cells from HIV-infected patients fail to produce granulysin in response to IL-2 activation. The present studies examined the mechanism of delayed production of granulysin and the mechanism of the defect in HIV patients. We demonstrate that IL-2 initially requires both STAT5 and PI3K activation to increase expression of IL-2Rβ, produce granulysin, and kill C. neoformans. The increased expression of IL-2Rβ precedes granulysin, and preventing the increased expression of IL-2Rβ using small interfering RNA knockdown abrogates granulysin expression. Moreover, following the increased expression of IL-2Rβ, blocking subsequent signaling by IL-2 using IL-2Rβ-specific blocking Abs abrogates expression of granulysin. Finally, CD4+ T cells from HIV-infected patients, who are defective in both STAT5 and PI3K signaling, fail to express IL-2Rβ and fail to produce granulysin. These results suggest that IL-2 signals via PI3K and STAT5 to increase expression of IL-2Rβ, which in turn is required for production of granulysin. These results provide a mechanism to explain the “late” production of granulysin during normal T cell responses, as well as for defective granulysin production by CD4+ T cells in HIV-infected patients.

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“…A CFU assay was performed, as previously described (33)(34)(35). C. neoformans (2 ϫ 10 3 /well) were incubated with or without YT cells (E:T ϭ 200:1 to 500:1, unless otherwise specified).…”

Section: Anticryptococcal Activity Of Yt Cellsmentioning

confidence: 99%

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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Phenotypic and functional characterization of human lymphocytes activated by interleukin-2 to directly inhibit growth of Cryptococcus neoformans in vitro.

Abstract: Recently we demonstrated that the nonadherent (to plastic) fraction of human PBMC could be activated by

Cited by 82 publications

References 36 publications

T cells cooperate with passive antibody to modifyCryptococcus neoformansinfection in mice

T cells cooperate with passive antibody to modifyCryptococcus neoformansinfection in mice

Late Expression of Granulysin by Microbicidal CD4+ T Cells Requires PI3K- and STAT5-Dependent Expression of IL-2Rβ That Is Defective in HIV-Infected Patients

NK Cells Use Perforin Rather than Granulysin for Anticryptococcal Activity

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