CD4+ and CD8+ T Cells Kill Intracellular<i>Mycobacterium tuberculosis</i>by a Perforin and Fas/Fas Ligand-Independent Mechanism

Canaday, David H.; Wilkinson, Robert J.; Silver, Richard F.; Boom, W. Henry

doi:10.4049/jimmunol.167.5.2734

Cited by 181 publications

(150 citation statements)

References 58 publications

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“…We found that CD40/ CD40L interactions enhanced the CTL activity of CD8 ϩ T cells, providing a potential mechanism for this interaction between CD4 ϩ and CD8 ϩ T cells. CD40LT greatly increased expression of perforin and granulysin, but not that of FasL, by CD8 ϩ T cells, consistent with prior reports that human CD8 ϩ T cells lyse M. tuberculosis-infected monocytes primarily through the granule exocytosis pathway, whereas apoptosis through Fas and FasL interactions plays a minor role (17). This pathway is likely to be important in immune defenses against tuberculosis as granulysin has direct antimicrobial activity against M. tuberculosis, and the combination of perforin and granulysin results in killing of intracellular M. tuberculosis (5).…”

Section: Discussionsupporting

confidence: 79%

“…Nonadherent cells (95% CD8 ϩ ) were then collected, washed, and stained for granulysin and perforin as described (17). Briefly, cells were permeabilized with permeabilization buffer (BD PharMingen) for 30 min on ice, then washed with cell wash buffer (BD PharMingen) and incubated with anti-granulysin mAb, DH4 (18), antiperforin mAb, ␦G9 (Kamiya Biomedical, Seattle, WA) or isotype control mouse IgG1 (BD PharMingen), for 30 min, and then washed three times with cell wash buffer.…”

Section: Immunolabeling To Detect Ctl Effector Moleculesmentioning

confidence: 99%

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CD40 Ligand Trimer Enhances the Response of CD8+ T Cells to Mycobacterium tuberculosis

Samten

Wizel

Shams

et al. 2003

The Journal of Immunology

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We investigated the effect of recombinant CD40 ligand trimer (CD40LT) on the functional capacity of peripheral blood CD8+ T cells from healthy tuberculin reactors that were cultured with Mycobacterium tuberculosis-infected autologous monocytes. CD40LT enhanced the capacity of M. tuberculosis-responsive CD8+ T cells to produce IFN-γ by increasing the number of IFN-γ-producing CD8+ T cells and the amount of IFN-γ produced per cell. CD40LT-induced IFN-γ production was dependent on production of IL-12 and IL-18, but did not require IL-15. CD40LT up-regulated expression of the transcription factors phosphorylated CREB and c-Jun, both of which have been previously shown to stimulate IFN-γ mRNA transcription by binding to the IFN-γ promoter. CD40LT also enhanced the capacity of CD8+ T cells to lyse M. tuberculosis-infected monocytes, and increased CTL activity was associated with higher expression of perforin and granulysin, but not of Fas ligand. We conclude that CD40LT can enhance CD8+ T cell effector function in response to M. tuberculosis.

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Section: Discussionsupporting

confidence: 79%

Section: Immunolabeling To Detect Ctl Effector Moleculesmentioning

confidence: 99%

CD40 Ligand Trimer Enhances the Response of CD8+ T Cells to Mycobacterium tuberculosis

Samten

Wizel

Shams

et al. 2003

The Journal of Immunology

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“…Using computer algorithms, Klein et al identified three epitopes from the Ag85 complex that were recognized by BCG-vaccinated HLA-B*3501 individuals: a) an epitope shared by Ag85ABC (Ag85 110-118 ) b) Ag85C 268-276 ; and Ag85B [204][205][206][207][208][209][210][211][212] (110). An interesting strategy for the identification of mycobacterial epitopes that are presented by human class I MHC is to use transgenic mice that express HLA-A*0201 (109).…”

Section: Respectively)mentioning

confidence: 99%

Mycobacterium tuberculosis-Specific CD8+ T Cells and Their Role in Immunity

2006

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There are more cases of tuberculosis in the world today than at anytime in history. The global epidemic has generated intense interest into the immunological mechanisms that control infection. While CD4 + T cells play a critical role in host immunity to Mycobacterium tuberculosis, there is considerable interest in understanding the role of other T cell subsets in preventing disease development following infection. CD8 + T cells are required for optimum host defense following M. tuberculosis infection, which has led to investigation of how this protective effect is mediated. A critical review of recent literature regarding the role of CD8 + T cells in protective immunity to M. tuberculosis infection is now required to address the strengths and weaknesses of these studies. In this review, we evaluate the evidence that CD8 + T cells are critical in immunity to M. tuberculosis infection. We discuss the specific mycobacterial proteins that are recognized by CD8 + T cells elicited during infection. Finally, we examine the effector mechanisms of CD8 + T cells generated during infection and synthesize recent studies to consider the protective roles that these T cells serve in vivo.

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“…Another important function of CTL and NK cells is the well-established but less well-known ability to participate in the direct killing of pathogens. Both CTL and NK cells or their products kill a broad range of bacteria, parasites, and fungi (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In particular, NK cells and CTL mediate direct antifungal activity against the opportunistic fungal pathogen Cryptococcus neoformans (15)(16)(17)(18).…”

mentioning

confidence: 99%

Perforin-Dependent Cryptococcal Microbicidal Activity in NK Cells Requires PI3K-Dependent ERK1/2 Signaling

Wiseman¹,

Ling²,

Marr³

et al. 2007

The Journal of Immunology

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Previously, NK cells have been reported to kill the opportunistic fungal pathogen Cryptococcus neoformans through a perforin-dependent mechanism; however, the receptor and signaling involved are unknown. In this report we sought to identify the signaling pathways activated and required for direct perforin-mediated killing of microbes. In this study, using the NK-like cell line YT and primary peripheral blood NK cells, it is demonstrated that YT cells kill C. neoformans and that the killing is accompanied by the activation of PI3K. We demonstrate that inhibition of either the catalytic subunit (using a pharmacological inhibitor) or the α-regulatory subunit (using small interfering RNA knockdown) of PI3K significantly inhibited the killing of C. neoformans. Downstream of PI3K, ERK1/2 was activated in a PI3K-dependent fashion and was required for cryptococcal killing. Furthermore, we demonstrate that perforin release from YT cells can be detected by 4 h after contact of the YT cells with C. neoformans and that the release of perforin is blocked by pharmacological inhibition of either PI3K or ERK1/2. Defective degranulation is rooted in the inability to polarize perforin-containing granules toward the target. Finally, we demonstrate that PI3K-ERK1/2-dependent signaling is activated and required for the killing of C. neoformans by primary NK cells. Taken together, these data identify a conserved PI3K-ERK1/2 pathway that is used by NK cells during the direct killing of C. neoformans and demonstrate that the pathway is essential in the formation and activation of the microbicidal mechanism.

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CD4+ and CD8+ T Cells Kill IntracellularMycobacterium tuberculosisby a Perforin and Fas/Fas Ligand-Independent Mechanism

Cited by 181 publications

References 58 publications

CD40 Ligand Trimer Enhances the Response of CD8+ T Cells to Mycobacterium tuberculosis

CD40 Ligand Trimer Enhances the Response of CD8+ T Cells to Mycobacterium tuberculosis

Mycobacterium tuberculosis-Specific CD8+ T Cells and Their Role in Immunity

Perforin-Dependent Cryptococcal Microbicidal Activity in NK Cells Requires PI3K-Dependent ERK1/2 Signaling

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