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Heat shock proteins as mediators of aggregation-induced 'danger' signals: implications of the slow evolutionary fine-tuning of sequences for the antigenicity of cancer cells

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CELL STRESS & CHAPERONES 1999年第4期4卷 205-210页

作者： Forsdyke, DR Queens Univ Dept Biochem Kingston ON K7L 3N6 Canada

Organisms 'tune' to their environment through adaptations which confer a selective advantage. However, in complex systems, a primary change of positive adaptive value might have multiple minor secondary effects, usually of negative adaptive value, which could invoke further counter-adaptations. This 'fine-tuning', a 'debugging', mainly at the intracellular level, would appear an evolutionary burden detracting from the positive nature of the primary change. However, if the primary mutation is in a potential oncogene, secondary, short-term effects may include the recruitment, in an apparently random manner, of unmutated non-oncogene products into the antigenic repertoire of the cancer cell. This 'danger' signal, provided by the co-aggregation of oncogene and non-oncogene products, would be mediated by inducible heat-shock proteins (Hsps), and lead to display of corresponding MHC-peptide complexes. It was argued previously that T cells specific for peptides from most 'self' intracellular antigens are not eliminated during T cell 'education', and so would be available for subsequent immune activation by the corresponding peptides. These considerations might explain why cancer specific antigens have been so elusive, why cancer antigenicity is often individual specific, and why therapeutic approaches involving complexes of peptides with Hsps may be successful. (C) 1999 Harcourt Publishers Ltd.

关键词：抗原肿瘤/代谢胞质溶胶/代谢进化分子基因表达调控肿瘤热休克蛋白质类/代谢免疫疗法肿瘤/免疫学 RNA/代谢受体抗原 T细胞/代谢 T淋巴细胞细胞毒性/代谢人类

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Induction of rapid histone degradation by the cytotoxic T lymphocyte protease granzyme A

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JOURNAL OF BIOLOGICAL CHEMISTRY 2001年第5期276卷 3683-3690页

作者： Zhang, D Pasternack, MS Beresford, PJ Wagner, L Greenberg, AH Lieberman, J Harvard Univ Sch Med Ctr Blood Res Boston MA 02115 USA Harvard Univ Massachusetts Gen Hosp Sch Med Boston MA 02115 USA Harvard Univ Sch Med Dept Pediat Boston MA 02115 USA Univ Manitoba Manitoba Inst Cell Biol Winnipeg MB R3E 0V9 Canada

The cytotoxic T lymphocyte protease granzyme A induces caspase-independent cell death in which DNA single-strand nicking is observed instead of oligonucleosomal fragmentation. Granzyme A is a specific tryptase that concentrates in the nucleus of targeted cells and synergistically enhances DNA fragmentation induced by the caspase activator granzyme B. Here we show that granzyme A treatment of isolated nuclei enhances DNA accessibility to exogenous endonucleases. In vitro and after cell loading with perforin, GrnA completely degrades histone H1 and cleaves core histones into similar to 16kDa fragments. Histone digestion provides a mechanism for unfolding compacted chromatin and facilitating endogenous DNase access to DNA during T cell and natural killer cell granule-mediated apoptosis.

关键词：细菌蛋白质类/代谢 COS细胞半胱氨酸天冬氨酸蛋白酶/拮抗剂和抑制剂半胱氨酸天冬氨酸蛋白酶/代谢细胞核/代谢染色质/代谢 DNA/代谢 DNA结合蛋白质类/代谢脱氧核糖核酸酶类/代谢颗粒酶类 HL-60细胞肝素/类似物和衍生物肝素/代谢组蛋白类/代谢 K562细胞膜糖蛋白类/代谢成孔毒素蛋白质类蛋白质结构三级/生理学蛋白聚糖类/代谢丝氨酸内肽酶类/代谢底物特异性 T淋巴细胞细胞毒性/酶学 T淋巴细胞细胞毒性/代谢胰蛋白酶/代谢动物人类

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Interferon-γ reduces melanosomal antigen expression and recognition of melanoma cells by cytotoxic T cells

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AMERICAN JOURNAL OF PATHOLOGY 2002年第2期160卷 521-528页

作者： Le Poole, IC Riker, AI Quevedo, ME Stennett, LS Wang, E Marincola, FM Kast, WM Robinson, JK Nickoloff, BJ Loyola Univ Med Ctr Canc Immunol Program Maywood IL 60153 USA Cardinal Bernardin Canc Ctr Dept Pathol Skin Oncol Res Program Maywood IL USA NIH Surg Branch Bethesda MD 20892 USA

In malignant melanoma, tumor-infiltrating lymphocytes are frequently reactive with melanosomal antigens. Achieving complete remissions by peptide therapy is frequently hampered by metastases evading immune recognition. The tumor microenvironment seems to favor reduced expression of target antigens by melanoma cells. Among candidate factors, interferon-gamma (rFN-gamma) (10(2) to 10(3) U/ml) suppressed expression of antigens MART-1, TRP-1, and gp100 by M14 melanoma cells as shown by immunohistology and fluorescence-activated cell sorting analysis, reducing MART-1 expression by >65%. Northern blot analysis revealed that reduced expression was regulated at the transcriptional level, demonstrating a 79% reduction in MART-1 transcript abundance after 32 hours of IFN-gamma treatment. To evaluate consequences of IFN-gamma exposure for immune recognition, MART-1-responsive T cells were reacted with pretreated HLA-matched melanoma cells. Cytotoxicity was reduced up to 78% by IFN-gamma pretreatment, and was restored by addition of MART-1 peptide AAGIGILTV for 2 hours. Examination of melanoma lesions by quantitative reverse transcriptase-polymerase chain reaction revealed up to 188-fold more abundant IFN-gamma transcripts when compared to control skin. Laser capture microdissection and immunohistology localized most IFN-gamma-producing T cells to the tumor stroma. Reduced MART-1 expression was frequently observed in adjacent tumor cells. Consequently, IFN-gamma may enhance inflammatory responses yet hamper effective recognition of melanoma cells.

关键词：抗原肿瘤/遗传学抗原肿瘤/免疫学抗原肿瘤/代谢细胞分离流式细胞术免疫组织化学干扰素γ/遗传学干扰素γ/代谢 MART-1抗原黑色素瘤/免疫学黑色素瘤/病理学显微镜检查/方法肿瘤蛋白质类/遗传学肿瘤蛋白质类/代谢 T淋巴细胞细胞毒性/免疫学 T淋巴细胞细胞毒性/代谢肿瘤细胞培养的人类

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Anti-third party CD8⁺ CTLs as potent veto cells:: Coexpression of CD8 and FasL is a prerequisite

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IMMUNITY 2000年第4期13卷 507-515页

作者： Reich-Zeliger, S Zhao, Y Krauthgamer, R Bachar-Lustig, E Reisner, Y Weizmann Inst Sci Dept Immunol IL-76100 Rehovot Israel

Several bone marrow cells and lymphocyte subpopulations, known as "veto cells," were shown to induce transplantation tolerance across major histocompatibility antigens. Recently, it has been suggested that anti-third party CTLs depleted of alloreactivity are endowed with marked veto activity and therefore might potentially facilitate bone marrow allografting without graft versus host disease (GVHD). The veto mechanism is still obscure. While early studies emphasized the role of CD8-mediated apoptosis, more recent evidence indicates a role for Fas-FasL. In the present study we show, by using blocking anti-CD8 antibody, by generating CTLs from FasL or perforin mutated mice, and by gene transfer of FasL, that the veto activity of anti-third party CD8(+) CTLs is dependent upon the simultaneous expression of both CD8 and FasL.

关键词：细胞凋亡/遗传学细胞凋亡/免疫学细胞培养的细胞毒性免疫/遗传学剂量效应关系免疫 Fas配体蛋白质淋巴细胞活化/遗传学淋巴细胞培养试验混合膜糖蛋白类/生物合成膜糖蛋白类/生理学小鼠近交BALBC 小鼠近交C3H 小鼠近交C57BL 小鼠近交MRLlpr 小鼠基因敲除小鼠转基因种特异性 T淋巴细胞亚群/细胞学 T淋巴细胞亚群/免疫学 T淋巴细胞亚群/代谢 T淋巴细胞细胞毒性/细胞学 T淋巴细胞细胞毒性/免疫学 T淋巴细胞细胞毒性/代谢动物女(雌)性小鼠

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ISOLATION OF MONONUCLEAR CYTOTOXIC-CELLS FROM CATTLE VACCINATED AGAINST FOOT-AND-MOUTH-DISEASE

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ARCHIVES OF VIROLOGY 1992年第3-4期122卷 293-306页

作者： AMADORI, M ARCHETTI, IL VERARDI, R BERNERI, C SPEDALI CIVIL BRESCIA BIOTECHNOL LAB BRESCIA ITALY

Mononuclear cells from peripheral blood leucocytes of foot-and-mouth disease (FMD) vaccinated cattle underwent blast transformation after in vitro culture with purified, inactivated, 146 S FMD virus antigen. From the prolonged culture of blast cells in medium with Interleukin-2 (5-10 U/ml), CD 45-positive effector cells were derived, which showed a potent, non MHC-restricted activity against virus-infected cells, the extent of which was inversely correlated with multiplicity of infection (MOI). Extensive characterization of effector cells by means of monoclonal antibodies (MAbs) in flow cytometry, lysis of various cell populations with MAbs and complement, Fc receptor analysis and Cr-51 release assays indicated that the isolated cells share some phenotypic and functional features of the human and murine Large Granular Lymphocyte/Natural Killer (N.K.) lineage.

关键词：抗体单克隆/免疫学抗体病毒/免疫学口蹄疫病毒属/免疫学细胞分离细胞培养的杀伤细胞天然/免疫学淋巴细胞活化受体 Fc/代谢 T淋巴细胞细胞毒性/免疫学 T淋巴细胞细胞毒性/代谢疫苗减毒病毒疫苗/投药和剂量病毒疫苗/免疫学病毒复制动物牛

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Conversion of a T cell antagonist into an agonist by repairing a defect in the TCR/peptide/MHC interface: Implications for TCR signaling

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IMMUNITY 2000年第4期13卷 475-484页

作者： Baker, BM Gagnon, SJ Biddison, WE Wiley, DC Harvard Univ Dept Mol & Cellular Biol Cambridge MA 02138 USA Howard Hughes Med Inst Cambridge MA 02138 USA NINDS Mol Immunol Sect Neuroimmunol Branch NIH Bethesda MD 20892 USA

The structure of the A6 alpha beta TCR/HTLV-1 Tax-peptide/MHC I complex with proline 6 of Tax substituted with alanine (P6A), an antagonist, is nearly identical to the structure with wild-type Tax agonist. Neither the proline in the agonist nor the alanine in the antagonist is contacted by the alpha beta TCR. Here, we demonstrate that antagonist activity of P6A is associated with low affinity of the A6 alpha beta TCR for Tax-P6A/HLA-A2. We show that stepwise repair of a packing defect in the TCR/MHC interface using N-alkylated amino acids results in stepwise increases in TCR affinity and activity. Kinetic and thermodynamic measurements suggest that for some ligands the range of T cell outcomes does not correlate with either their alpha beta TCR affinity or the half-life of the alpha beta TCR/peptide/MHC complex.

关键词：丙氨酸/代谢氨基酸取代/免疫学细胞培养的结晶学 X线细胞毒性试验免疫基因产物 tax/化学基因产物 tax/代谢甘氨酸/代谢 HLA-A2抗原/代谢配体肽类/化学肽类/代谢脯氨酸/代谢蛋白质结合/免疫学蛋白质折叠受体抗原 T细胞 α-β/激动剂受体抗原 T细胞 α-β/拮抗剂和抑制剂受体抗原 T细胞 α-β/代谢受体抗原 T细胞 α-β/生理学肌氨酸/代谢信号传导/免疫学 T淋巴细胞细胞毒性/免疫学 T淋巴细胞细胞毒性/代谢热力学超速离心法/方法水人类

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Activation of infiltrating cytotoxic T lymphocytes and lymphoma cell apoptotic rates in gastric MALT lymphomas -: Differences between high-grade and low-grade cases

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AMERICAN JOURNAL OF PATHOLOGY 1999年第3期155卷 823-829页

作者： Guidoboni, M Doglioni, C Laurino, L Boiocchi, M Dolcetti, R Ctr Riferimento Oncol Div Expt Oncol 1 I-33081 Aviano PN Italy Belluno City Hosp Dept Pathol Belluno Italy

In this study, we have characterized infiltrating T lymphocytes from 13 low-grade and 17 high-grade primary gastric MALT lymphomas by immunohistochemistry, with particular regard to the presence, activation, and topographic distribution of cytotoxic effecters. Although the prevalence of CD4+ and CD8+ cells was similar in low- and high-grade lymphomas, higher numbers of TIA-1+ cytotoxic effecters were found in this latter group of cases (11.6 versus 7.8%;P = 0.004), Activation of CD8+ cytotoxic T lymphocytes (CTLs) was significantly more pronounced in high than in low-grade lymphomas, as shown by immunostaining for perforin (8.7 versus 4.0%;P = 0.001) and granzyme-B (GrB) (8.7% versus 3.0%;P < 0.0001), Of note, CD20/GrB double labeling showed that high-grade lymphomas carried a markedly higher content (about ninefold) of activated CTLs relative to the number of CD20+ lymphoma B cells (0.081 +/- 0.076 versus 0.009 +/- 0.011;P < 0.0001). Moreover, high-grade lymphomas showed significantly increased apoptotic rates compared to low grade cases (5.3 and 1.1% of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, respectively;P < 0.0001). In the whole series, the percentage of GrB+ cells and the GrB+/CD20+ ratio showed a strong Linear correlation with the number of TUNEL-labeled cells. These findings, together with the frequent colocalization of CTLs and TUNEL+ neoplastic cells, suggested that apoptotic death of lymphoma cells may be due at least in part to the killing by cytotoxic effecters. Our results are consistent with the occurrence of host antitumor cell-mediated immune responses in gastric MALT lymphomas, Moreover, the finding of stronger cytotoxic responses in high than in low-grade cases is of potential usefulness in the design of more effective therapeutic strategies for the management of these disorders.

关键词：抗原 CD20/代谢抗原 CD56/代谢细胞凋亡 CD4-CD8比值细胞计数 GRB10衔接蛋白质免疫组织化学原位缺口末端标记淋巴细胞活化/免疫学淋巴细胞肿瘤浸润/免疫学淋巴细胞肿瘤浸润/代谢膜蛋白质类/代谢 Poly(A)结合蛋白质类蛋白质类/代谢 RNA结合蛋白质类/代谢胃肿瘤/免疫学胃肿瘤/病理学 T淋巴细胞细胞毒性/免疫学 T淋巴细胞细胞毒性/代谢人类

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Acute generalized exanthematous pustulosis - Role of cytotoxic T cells in pustule formation

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AMERICAN JOURNAL OF PATHOLOGY 2002年第6期161卷 2079-2086页

作者： Schmid, S Kuechler, PC Britschgi, M Steiner, UC Yawalkar, N Limat, A Baltensperger, K Braathen, L Pichler, WJ Inselspital Bern Clin Rheumatol & Clin Immunol Allergol CH-3010 Bern Switzerland Inselspital Bern Clin Dermatol CH-3010 Bern Switzerland Univ Bern Dept Pharmacol Bern Switzerland Modex Therapeut Lausanne Switzerland

Extensive formation of nonfollicular sterile pustules on erythematous background combined with fever and peripheral blood leukocytosis are the characteristics of acute generalized exanthematous pustulosis. This uncommon eruption most often is an allergic reaction because of drugs such as aminopenicillins and sulfonamides inter alia. We recently demonstrated the important role of drug-specific T cells in the pathogenesis of this disease, showing that they produce high amounts of the neutrophil-attracting chemokine interleukin-8 and therefore stand out as a special subgroup of T cells, differing from the usual Th1 and Th2 subsets. In this study we use immunohistochemistry as well as cytotoxicity assays (4- and 18-hour assays) and fluorescence-activated cell-sorting analysis of drug-specific circulating T cells and of cells eluted from the skin of five patients with acute generalized exanthematous pustulosis, to analyze whether cytotoxic T-cell functions are important in the pathogenesis of this disease, in particular for the formation of vesicles. The data reveal that drug-specific CD4(+) as well as CD8(+) T cells both are activated and cytotoxic;perforin/granzyme B and to a variable degree the Fas/FasL-killing mechanism is involved in tissue destruction. These features allow the formation of vesicles. Additional secretion of interleukin-8 by T cells and keratinocytes attracts neutrophils that fill the vesicles and transform them into pustules.

关键词：抗原 CD95/药理学活组织检查细胞毒性试验免疫药疹/代谢药疹/病理学疹/病理学 Fas配体蛋白质颗粒酶类 HLA-DR抗原/代谢刺激剂/药理学淋巴细胞活化膜糖蛋白类/药理学穿孔素表型成孔毒素蛋白质类受体白细胞介素2/代谢丝氨酸内肽酶类/药理学皮肤/病理学 T淋巴细胞亚群/代谢 T淋巴细胞细胞毒性/代谢动物人类小鼠

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The identification of myriocin-binding proteins (vol 6, pg 221, 1999)

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CHEMISTRY & BIOLOGY 1999年第6期6卷 R186-R186页

作者： Chen, JK Lane, WS Schreiber, SL Howard Hughes Medical Institute Department of Chemistry and Chemical Biology Harvard University 12 Oxford Street Cambridge MA 02138 USA Harvard Microchemistry Facility Harvard University 16 Divinity Avenue Cambridge MA 02138 USA

BACKGROUND: Myriocin is a natural product that potently induces apoptosis of a murine cytotoxic T lymphocyte cell line (CTLL-2) and inhibits a serine palmitoyltransferase (SPT) activity that has been detected in cell extracts and is thought to initiate sphingolipid biosynthesis. Because SPT has never been biochemically purified and a comprehensive appraisal of myriocin-binding proteins has not been conducted, we isolated specific targets using myriocin-based affinity chromatography. RESULTS: Myriocin derivatives were synthesized and evaluated using CTLL-2 proliferation and SPT activity assays. Guided by these results, affinity chromatography matrices were prepared and two specific myriocin-binding proteins were isolated from CTLL-2 lysates. Analyses of these polypeptides establish conclusively that they are murine LCB1 and LCB2, mammalian homologs of two yeast proteins that have been genetically linked to sphingolipid biosynthesis. CONCLUSION: The ability of myriocin-containing matrices to bind factors that have SPT activity and the exclusive isolation of LCB1 and LCB2 as myriocin-binding proteins demonstrates that the two proteins are directly responsible for SPT activity and that myriocin acts directly upon these polypeptides.

关键词：氨基酸序列抗生素类抗肿瘤/化学合成抗生素类抗肿瘤/代谢抗生素类抗肿瘤/药理学细胞培养的脂肪酸类单不饱和/化学合成脂肪酸类单不饱和/代谢脂肪酸类单不饱和/药理学分子序列数据序列分析丝氨酸C-棕榈酰转移酶 T淋巴细胞细胞毒性/药物作用 T淋巴细胞细胞毒性/代谢动物小鼠

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