Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice

Kägi, David; Ledermann, Birgit; Bürki, Kurt; Seiler, Peter; Odermatt, Bernhard; Olsen, Kristin J.; Podack, Eckhard R.; Zinkernagel, Rolf M.; Hengartner, Hans

doi:10.1038/369031a0

Cited by 1,621 publications

(1,210 citation statements)

References 46 publications

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“…It is known that perforin/ granzyme and Fas/FasL-mediated killing pathways are the main mechanisms of effectors to eliminate target cells, like transformed cells. [3][4][5] In the absence of these cytolytic functions, gIFN and TNF-a are also responsible for the antitumor effects of immunocytes. [6][7][8] Granules containing the pore-forming protein perforin and granzymes, which are serine proteinases, are released from CTL to target cells that undergo apoptosis.…”

Section: Ytotoxic T Cells (Ctls) and Natural Killer (Nk) Cellsmentioning

confidence: 99%

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In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

et al. 2004

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Perforin/granzyme B-and Fas/FasL-mediated killing pathways are the main effector mechanisms of CTL and NK cells in antitumor immune responses. In this study, we investigated the relative role of these two lytic mechanisms in protection of the host from tumor progression, as well as spontaneous metastasis, using the D122 Lewis lung carcinoma and its gene-modified cells. Utilizing perforin knockout mice (B6-PKO) and Fas and FasL mutant (B6-MRL and B6-Smn) mice, we found that perforin expression in the host plays a crucial function in the prevention of metastasis. However, local tumor rejection of an H-2K b and B7-1 transfectant, 39.5-B7 cells, was not dependent either on perforin or Fas/FasL expression in vivo. In addition, CTL lysis of 39.5-B7 cells was independent of perforin and Fas/FasL interactions in 18-hour in vitro assays. We also confirmed that CD8 T-cells were responsible for rejecting 39.5-B7 local tumors, yet cytokines, TNF-a and gIFN were not involved in tumor rejection in vivo. Furthermore, blocking assays using caspase inhibitors (zVAD-fmk, zIETD-fmk and zLEHD-fmk) showed that, whereas caspase activation was partially required to induce 39.5-B7 lysis mediated by the perforin-dependent pathway, 39.5-B7 lysis by CTLs through the perforin-independent mechanism required caspase activation. Thus, these results suggested that perforin, Fas/FasL, gIFN and TNF-a independent lytic mechanisms, mediated by CD8 T cells, have a crucial role in rejection of 39.5-B7 cells in vivo. Caspase activation is a pre requisite for apoptosis of targets by CTLs

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Section: Ytotoxic T Cells (Ctls) and Natural Killer (Nk) Cellsmentioning

confidence: 99%

“…4,18,19 Mice used for the experiments were generally 8-12 weeks old and were maintained in the animal facility of the Weizmann Institute of Science.…”

Section: Micementioning

confidence: 99%

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

et al. 2004

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“…B6 mice were ordered from Jackson Laboratories (Bar Harbor, ME) whereas pko mice on the B6 background were bred in the animal colony from stock provided by Dr. H. Hentgartner [42]. Caspase 3 -/-mice and heterozygous littermates [24] and caspase 9 -/-/RAG2 -/-and wild-type/RAG2 -/-chimeras [29] were generated as described.…”

Section: Animalsmentioning

confidence: 99%

Perforin‐dependent activation‐induced cell death acts through caspase 3 but not through caspases 8 or 9

et al. 2003

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Activation-induced cell death (AICD) is a phenomenon in which activated T cells undergo apoptosis upon restimulation. We are studying a form of AICD that can occur before cells become competent to die by Fas (hence "early" AICD) and which depends on the presence of perforin. Previous studies indicate that it does not occur through granule exocytosis but via some endogenous pathway. We here investigate a possible role for caspases. Caspase 3 -/-cells were protected, suggesting a role for caspase 3 in early AICD. After recrosslinking, caspase 3 activity could be detected in cell lysates between 3 and 12 h, and CD8 + T cells became annexin V-positive between 15 and 18 h. Blocking anti-Fas ligand antibody failed to inhibit death, and no processing of either caspase 8 or caspase 9 was detected in recrosslinked cells. Furthermore, T cells lacking functional caspase 9 continued to die in early AICD. Thus, perforin-dependent early AICD appears to require activation of caspase 3, but not caspases 8 or 9. As perforin has no intrinsic catalytic abilities, we propose that it releases some endogenous activity that can activate caspase 3.

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“…Upon activation, they directly eliminate target cells through exocytosis of perforin-and granzyme-containing granules, or by Fas ligand (CD178) or TRAIL pathways [3][4][5][6][7]. NK cells also produce cytokines and chemokines, which enable them to recruit non-specific haematopoetic cells, activate dendritic cells and prime adaptive lymphocytes [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Continuous CD27 triggering in vivo strongly reduces NK cell numbers

et al. 2010

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NK cells are important mediators of the early defense. In mice, immature and mature NK (mNK) cells constitutively express the TNF receptor family member CD27; however, mNK cells eventually lose CD27 expression and become resting NK cells. Interaction of CD27 with its ligand, CD70, enhances proliferation and effector functions of NK cells. We used mice that constitutively express CD70 on B cells (CD70-Tg) to study the in vivo effects of continuous triggering of CD27 on NK cells. Continuous CD70-CD27 interaction resulted in strongly down-modulated CD27 expression on NK cells and gradually reduced absolute NK cell numbers. This reduction was most prominent in the mNK cell subpopulation and was at least partially due to increased apoptosis. Residual NK cells showed lower expression of activating Ly49 receptors and normal (liver) or decreased (spleen) IFN-c production. Nevertheless, NK cells from CD70-Tg mice displayed higher YAC-1 killing capacities. CD70-Tg NK cells exhibited up-regulated expression of NKG2D, which is in accordance with the increased YAC-1 lysis, as this is mainly NKG2D-dependent. Taken together, this study is the first to demonstrate that continuous CD70 triggering of CD27 on NK cells in vivo results in a severe reduction of NK cells. On a single cell basis, however, residual NK cells display enhanced cytotoxicity.Key words: CD70-Tg mice . Cytotoxicity . Differentiation Supporting Information available online Introduction NK cells are large granular lymphocytes of the innate immune system that play a crucial role in the early host defense [1,2]. Upon activation, they directly eliminate target cells through exocytosis of perforin-and granzyme-containing granules, or by Fas ligand (CD178) or TRAIL pathways [3][4][5][6][7]. NK cells also produce cytokines and chemokines, which enable them to recruit non-specific haematopoetic cells, activate dendritic cells and prime adaptive lymphocytes [8][9][10][11]. As such, NK cells bridge between innate and adaptive immunity. The functional behaviour of NK cells is regulated by the engagement of a broad array of activating and inhibitory cell membrane receptors (reviewed in Lanier [12]).The BM is considered to be the main site for NK cell development [13][14][15][16]. Here, multipotent haematopoietic precursors generate NK cell precursors (NKP). Murine NKP are lineage(lin) À CD122 1 NK1.1 À CD49b À . NKP differentiate into immature NK (iNK) cells, which exhibit a lin À CD122 1 NK1. [20,21]. Interestingly, Hayakawa and Smyth [22]showed that within the TCR b À NK1.1 1 gated NK cell pool there is a CD11b low subpopulation, including both iNK and early mNK cells, which is homogenously CD27 high (referred to as subset 1), whereas the CD11b high population of late mNK cells consists of two functionally distinct subsets: i.e. CD27 high (referred to as subset 2) and CD27 low (referred to as subset 3). NK cells from subset 1 are the first NK cell population detected after BM transplantation and they give rise to subset 2 after adoptive transfer. Subset 2 consists of fu...

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Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice

Cited by 1,621 publications

References 46 publications

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

Perforin‐dependent activation‐induced cell death acts through caspase 3 but not through caspases 8 or 9

Continuous CD27 triggering in vivo strongly reduces NK cell numbers

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