Disease relevance of Prf1

• Both Prf1 and Gzms drastically affected the outcome of murine cytomegalovirus (MCMV) infection [1].
• Perforin-deficient mice failed to clear lymphocytic choriomeningitis virus in vivo, yet substantial killing activity still remained in perforin-free CTLs in vitro, indicating the presence of (a) further lytic pathway(s) [2].
• Approximately half the cohort of perforin gene-targeted mice succumbed to spontaneous disseminated B cell lymphomas and in mice that also lacked beta2m, the lymphomas developed earlier (by more than 100 d) and with greater incidence (84%) [3].
• Although neither pathway is critical in the development of colitis, perforin does have a measurable influence on disease in the BM-->Tg26 colitis model [4].
• Consequences of Fas-ligand and perforin expression by colon T cells in a mouse model of inflammatory bowel disease [4].

Psychiatry related information on Prf1

• We conclude that the mechanism underlying the suppression of NK and LAK cytolytic activity by alcohol consumption involves the collective reduction of target-induced release, activity, and expression of perforin and granular proteases [5].
• Effect of electric foot shock and psychological stress on activities of murine splenic natural killer and lymphokine-activated killer cells, cytotoxic T lymphocytes, natural killer receptors and mRNA transcripts for granzymes and perforin [6].
• The role of perforin in the local defense mechanisms against influenza virus infection was investigated [7].
• The use of Ab2 allowed us to show that B6/1 Id is expressed in 4 to 32% of serum antibodies during the primary and secondary immune responses of BALB/c mice to CL [8].

High impact information on Prf1

• The granule exocytosis pathway utilizes perforin to traffic the granzymes to appropriate locations in target cells, where they cleave critical substrates that initiate DNA fragmentation and apoptosis; granzymes A and B induce death via alternate, nonoverlapping pathways [9].
• Analyses of mice deficient in perforin and/or Fas demonstrate that cytolysis is critical for immunity against some, but not all, infections and also reveal the contribution of cytolysis to the pathogenesis of disease [10].
• The protective role of the perforin-dependent pathway has been shown for infection with the noncytopathic lymphocytic choriomeningitis virus, for infection with Listeria monocytogenes, and for the elimination of tumor cells by T cells and NK cells [11].
• LCMV-induced immunopathology and autoimmune diabetes have been found to require perforin-expression [11].
• In contrast, perforin-dependent cytotoxicity is not involved in protection against the cytopathic vaccinia virus and vesicular stomatitis virus [11].

Chemical compound and disease context of Prf1

• Primary rejection of class I-deficient RMA-S lymphoma cells expressing the NKG2D ligand, retinoic acid early inducible-1beta, was critically dependent upon NK cell perforin and occurred independently of T cells [12].
• Seeligeriolysin O, a cholesterol-dependent cytolysin of Listeria seeligeri, induces gamma interferon from spleen cells of mice [13].
• Also, secondary immunization of TCR transgenic perforin-deficient mice with the lymphocytic choriomeningitis virus glycoprotein-derived epitope peptide leads to an increased proliferation of transgenic CD8(+) T cells, that is not explained by failure to deplete professional antigen-presenting cells [14].
• Although the development of bleomycin induced pneumopathy was not completely prevented, the pathological grade of inflammation and fibrosis, and the number of apoptotic cells in lung tissue, were significantly decreased in perforin knockout mice compared with wild-type mice [15].
• Perforin mRNA expression in the inflamed tissues of NZB/W F1 lupus mice decreases with methylprednisolone treatment [16].

Biological context of Prf1

• Perforin has also been localized in granulated metrial gland (GMG) cells of the murine embryo implantation site by light microscopic immunostaining [17].
• Perforin- and MHC class II-deficient mice (with functional CD8(+) T cells and perforin molecules and an H-2(b) haplotype) had comparable demyelination and genotype, however, only the latter showed severe clinical disease [18].
• Previous work showed that neurons of the CNS are protected against perforin-mediated T cell cytotoxicity, but are susceptible to Fas-mediated apoptosis [19].
• We conclude that 1) the inhibitory effect of RAP at the level of the IL-2R is incomplete; and 2) the suppressive effect of RAP on CTL induction is only partly due to inhibition of Gzm B and perforin gene expression [20].
• Similar rates of DNA fragmentation were induced in TNP-modified ICE -/- and ICE +/+ T lymphoblast targets by perforin -/- TNP-modified, H-2b target cell-specific CTL [21].

Anatomical context of Prf1

• This distinction in outcome depended on accumulation of mononuclear cells and T cells in infected Prf1(-/-) mice [1].
• We have tested the use of NOD- Rag1 null Prf1 null mice as recipients in a long-term xenograft assay for human hematopoietic stem cells (HSCs) by adopting Yoder and colleagues' method of conditioned newborn mice, with minor modifications [22].
• Transfer of perforin-competent NK cells restores the ability of PKO mice to clonally expand CD8 CTL in response to gp96-Ig [23].
• Thus, perforin-dependent cytotoxicity is not only a crucial mechanism of both cytotoxic T lymphocyte- and NK-dependent resistance to injected tumor cell lines, but also operates during viral and chemical carcinogenesis in vivo [24].
• RESULTS: Colon cytotoxic T lymphocyte displayed both Fas- and perforin-dependent killing [4].

Associations of Prf1 with chemical compounds

• Pregnant NOD- Rag1 null Prf1 null dams were treated with busulfan 22.5 mg/kg [22].
• Perforin has been located in all of the granules, whereas gold particles corresponding to serine esterases have been found in most of the granules [17].
• The cytotoxicity was dose-dependently inhibited by either a Con A ligand, alpha-methyl mannoside, or a perforin inhibitor, concanamycin A (CMA), but not by anti-Fas ligand antiserum [25].
• On the other hand, the cytotoxic activity of AIM against the allografts was dose dependently inhibited by EGTA; and the suppression was restored by the addition of Ca2+, but not Mg2+, implying the involvement of perforin in the cytotoxicity [26].
• In contrast, brefeldin A blocked the Fas-based cytotoxicity, but only marginally reduced the perforin-based cytotoxicity [27].

Physical interactions of Prf1

• Alveolar epithelial cells efficiently process and present overlapping viral epitopes, and CD8+ T-cell recognition of these class I major histocompatibility complex-restricted epitopes resulted in cytotoxicity of the alveolar cells by both wild-type and perforin-deficient T cells [28].
• The cytolysin bound erythrocyte membranes in temperature-independent manner and then lysed cells temperature-dependently [29].

Enzymatic interactions of Prf1

• Perforin adsorbed to resistant cells was cleaved by trypsin into a 55-kDa (C-terminal) and a 10- to 15-kDa (N-terminal) fragment, whereas this cleavage was not found on tumor cell-bound perforin [30].

Co-localisations of Prf1

• In PM and IBM, PF positive cells were colocalized with GA positive cells and occasionally invaded into the non-necrotic muscle fibres [31].

Regulatory relationships of Prf1

• Trinitrophenyl (TNP)-modified, H-2b target cell-specific CTL were generated from perforin-deficient mice and were found to induce DNA fragmentation only in target cells expressing functional Fas receptors [21].
• Bcl-2 prevents apoptosis induced by perforin and granzyme B, but not that mediated by whole cytotoxic lymphocytes [32].
• Furthermore, virus-immune CTL with functional FasL and perforin (gzmAxB(-/-)) are more potent in causing target cell apoptosis in vitro than those expressing FasL alone (perfxgzmAxB(-/-)) [33].
• Perforin-dependent activation-induced cell death acts through caspase 3 but not through caspases 8 or 9 [34].
• IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN-gamma [35].

Other interactions of Prf1

• Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways [2].
• Here we report that both perforin-deficient and Fas-ligand-deficient CTLs show impaired lytic activity on all target cells tested [2].
• We evaluated the development of spontaneous tumors in mice lacking beta-2 microglobulin (beta2m; and thus MHC class I, CD1d, and CD16) and/or perforin, since these tumor cells would be expected to activate innate effector cells [3].
• Granzyme B-independent cytotoxicity is therefore partially accounted for by the Fas pathway and partially by another perforin-dependent mechanism [36].
• Moreover, SPI-CI can protect cells from purified perforin/GrM-induced lysis [37].

Analytical, diagnostic and therapeutic context of Prf1

• Wt and either perforin-deficient or FasL-deficient CD8+ T cells expanded early after transplantation followed by a contraction phase in which the majority of expanded CD8+ T cells were eliminated [38].
• Results from the double immunogold technique indicate that perforin and serine esterases colocalize to most of the same granules in GMG cells [17].
• Tumor regression after adoptive transfer of effector T cells is independent of perforin or Fas ligand (APO-1L/CD95L) [39].
• The complete depletion of perforin in LAK cells derived from perforin gene-knockout mice was further confirmed by immunoelectron microscopy using anti-perforin antiserum [40].
• Cytototoxic T lymphocyte-induced apoptosis can occur either through the directed exocytosis of granzyme B and perforin or via ligation of Fas [41].

References