Resistance of cytotoxic T lymphocytes to the lytic effects of their toxic granules.

Verret, C R; Firmenich, A. A.; Kranz, David M.; Eisen, Herman N.

doi:10.1084/jem.166.5.1536

Cited by 60 publications

(32 citation statements)

References 33 publications

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“…Treatment of the tumor cells with a poison (5 mM 2-deOG, 1.5 mM NaN 3 , 1 mM KCN) to make them more sensitive to granule killing resulted in significant increase in lysis ( Fig. 1C) (16). However, preincubation with bortezomib by itself or with the poison did not result in any increase in lytic capability of the granules.…”

Section: Sensitization Of Tumor Cells To Nk Cell-mediated Lysis By Pementioning

confidence: 86%

Sensitization of Tumor Cells to NK Cell-Mediated Killing by Proteasome Inhibition

Hallett

Ames

Motarjemi

et al. 2008

The Journal of Immunology

135

124

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Bortezomib is a proteasome inhibitor that has direct antitumor effects. We and others have previously demonstrated that bortezomib could also sensitize tumor cells to killing via the death ligand, TRAIL. NK cells represent a potent antitumor effector cell. Therefore, we investigated whether bortezomib could sensitize tumor cells to NK cell-mediated killing. Preincubation of tumor cells with bortezomib had no effect on short-term NK cell killing or purified granule killing assays. Using a 24-h lysis assay, increases in tumor killing was only observed using perforin-deficient NK cells, and this increased killing was found to be dependent on both TRAIL and FasL, correlating with an increase in tumor Fas and DR5 expression. Long-term tumor outgrowth assays allowed for the detection of this increased tumor killing by activated NK cells following bortezomib treatment of the tumor. In a tumor purging assay, in which tumor:bone marrow cell mixtures were placed into lethally irradiated mice, only treatment of these mixtures with a combination of NK cells with bortezomib resulted in significant tumor-free survival of the recipients. These results demonstrate that bortezomib treatment can sensitize tumor cells to cellular effector pathways. These results suggest that the combination of proteasome inhibition with immune therapy may result in increased antitumor efficacy.

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Section: Sensitization Of Tumor Cells To Nk Cell-mediated Lysis By Pementioning

confidence: 86%

Sensitization of Tumor Cells to NK Cell-Mediated Killing by Proteasome Inhibition

Hallett

Ames

Motarjemi

et al. 2008

The Journal of Immunology

135

124

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“…Although CTL effectively destroy other cells, they are relatively resistant to granule-mediated self destruction in vitro (45). Self protection of CTL against cytolytic granules may be explained by rapid appearance of cathepsin B on the CTL surface after TCR ligation, resulting in proteolysis of released perforin bound to the CTL membrane (46).…”

Section: Discussionmentioning

confidence: 99%

Distinct role of lymphocyte function-associated antigen-1 in mediating effective cytolytic activity by cytotoxic T lymphocytes

Anikeeva

Somersalo²,

Sims³

et al. 2005

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

150

155

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Lymphocyte function-associated antigen-1 (LFA-1) interaction with intercellular adhesion molecules (ICAMs) facilitates T cell antigen receptor (TCR)-mediated killing. To dissect TCR and LFA-1 contributions, we evaluated cytolytic activity and granule release by cytotoxic T lymphocytes (CTL) as well as intracellular granule redistribution and morphology of CTL stimulated with natural TCR ligand in the presence or absence of LFA-1 engagement. Although other adhesion mechanisms, e.g., CD2-CD58 interaction, could substitute for LFA-1 to trigger CTL degranulation, productive LFA-1 ligation was indispensable for effective target cell lysis by the released granules. LFA-1-mediated adhesion to glass-supported bilayers containing intercellular adhesion molecule-1 was characterized by a much larger junction area, marked by LFA-1 segregation, and a more compact cell shape compared with those observed for CD2-mediated adhesion to bilayers containing CD58. A larger contact induced by intercellular adhesion molecule 1 determined a unique positioning of granules near the interface. These data provide evidence that LFA-1 delivers a distinct signal essential for directing released cytolytic granules to the surface of antigenbearing target cells to mediate the effective destruction of these cells by CTL.cytolytic granules ͉ immunological synapse ͉ T cell receptor K illing of virus-infected cells by cytotoxic T lymphocytes (CTL) is triggered by interactions of T cell antigen receptor (TCR) with viral peptides presented by MHC class I proteins on the surface of infected cells and can be mediated by cytotoxic granule exocytosis or FasL-Fas interaction (1, 2). This is a sensitive response often requiring less than a dozen cognate peptide-MHC [complex of antigenic peptide with MHC protein (pMHC)] complexes on the target cell (3, 4). Although productive TCR engagement is necessary and essential to induce CTL cytolytic activity, other accessory and costimulatory molecules are thought to play a role in mediating CTL degranulation and effective cytolytic activity of released granules. For example, both lymphocyte function-associated antigen-1 (LFA-1) and CD2 contribute to CTL adhesion and killing of target cells (5). Ligation of LFA-1 on CTL by high densities of intercellular adhesion molecule-1 (ICAM-1) is sufficient to initiate large-scale molecular segregation and formation of peripheral supramolecular-activating cluster (6), which typically requires antigen for helper T cells (7,8) and CTL precursors (9). In contrast, ligation of CD2 with its natural ligand CD58 (5) mediates formation of a very small adhesion area by CTL (10). However, how specifically LFA-1, CD2, and other adhesion molecules mediate granuleinduced cytotoxicity has not been defined.Here we have investigated the role of productive LFA-1 engagement for antigen-induced granule release and target cell lysis in vitro as well as for granule polarization in CTL exposed to the glasssupported bilayer. We have found that, although blocking of LFA-1-ICAM-1 interaction abrogates ...

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“…Nevertheless, CTL themselves are largely resistant to lysis by other CTL (2)(3)(4)(5). Several mechanisms for the resistance of CTL to its own effector mechanisms have been proposed.…”

mentioning

confidence: 99%

Functional Segregation of the TCR and Antigen-MHC Complexes on the Surface of CTL

Mekala

Geiger

2003

The Journal of Immunology

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As CTL adhere to and lyze their targets, they extract cognate Ag-MHC and represent this on their own cell surface. Whether such self-presented cognate Ag stimulate the TCR of a CTL is uncertain. To analyze this, we examined TCR capping in response to self-presented Ag. We found that OVA peptide-specific OT-1 CTL that were pulsed with cognate peptide Ag did not cap their TCR, implying that the autologously presented MHC-Ag complex does not normally stimulate the TCR. However, this functional separation of the TCR and its ligand on the cell surface was not absolute. Treatment of Ag-pulsed OT-1 CTL with agents that alter cell surface charge, including trypsin, papain, tunicamycin, neuraminidase, and polybrene, allowed Ag-specific TCR capping. The TCR capped together with the restricting MHC molecule on the surface of the cell, implying an interaction between the TCR and cell-associated Ag. Further, the treated CTL underwent a time- and dose-dependent suicidal death that was both Fas- and perforin-dependent. Therefore, our results indicate that the association of the TCR with its MHC-peptide ligand on the surface of a CTL is normally proscribed by biophysical properties of the plasma membrane. Overcoming this restriction allows TCR stimulation and induces CTL effector functions and cell suicide.

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Resistance of cytotoxic T lymphocytes to the lytic effects of their toxic granules.

Cited by 60 publications

References 33 publications

Sensitization of Tumor Cells to NK Cell-Mediated Killing by Proteasome Inhibition

Sensitization of Tumor Cells to NK Cell-Mediated Killing by Proteasome Inhibition

Distinct role of lymphocyte function-associated antigen-1 in mediating effective cytolytic activity by cytotoxic T lymphocytes

Functional Segregation of the TCR and Antigen-MHC Complexes on the Surface of CTL

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