Natural killer cells and cytotoxic T lymphocytes are the main cell populations of the immune system able to directly kill target cells via cytotoxic granules. Different mammalian species may differ in specific features of their pore-forming protein (perforin) and granule-bound serine proteases (granzymes). One perforin gene (PRF1) and four genes encoding granzymes A, B, H, and K (GZMA, GZMB, GZMH, GZMK) were identified in the reference genomes of felids. The objective of this work was to characterize the genes PRF1, GZMA and GZMB in a panel of 17 felid species by next-generation re-sequencing. A search of available felid genomes (17 species) retrieved the coding sequences of these genes for comparison to our data. Both sets of sequences or their combinations (23 species) were used for phylogenetic and selection analyses. Nucleotide PRF1, GZMA and GZMB sequences showed high similarities between felid species (over 95% identity). All trees derived from coding sequences expressed phylogenetic relationships corresponding to the zoological taxonomy of the Felidae, except GZMA. No effects of positive selection were detected in the genes studied, however, effects of purifying selection were observed for PRF1 and GZMA. The conservation of PRF1 is in agreement with its critical biological function. The differentiation observed between granzyme sub-families may reflect an adaptation to pathogen variation. The need to maintain important gene functions and at the same time cope with various pathogens may lead to an equilibrium between positive and negative selective pressures acting on GZMB. The within-species variability in wild felid populations merits further investigation.

• Klíčová slova
• Felidae, NK cell, T cell, cytotoxic granule, granzyme, perforin,
• MeSH
• alely MeSH
• buňky NK * MeSH
• cytotoxické proteiny tvořící póry genetika   MeSH
• cytotoxické T-lymfocyty MeSH
• Felidae * genetika   MeSH
• fylogeneze MeSH
• granzymy genetika   MeSH
• lidé MeSH
• perforin genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytotoxické proteiny tvořící póry MeSH
• granzymy MeSH
• perforin MeSH

Cytotoxic T cells and natural killer cells can kill target cells based on their expression and release of perforin, granulysin, and granzymes. Genes encoding these molecules have been only poorly annotated in camelids. Based on bioinformatic analyses of genomic resources, sequences corresponding to perforin, granulysin, and granzymes were identified in genomes of camelids and related ungulate species, and annotation of the corresponding genes was performed. A phylogenetic tree was constructed to study evolutionary relationships between the species analyzed. Re-sequencing of all genes in a panel of 10 dromedaries and 10 domestic Bactrian camels allowed analyzing their individual genetic polymorphisms. The data showed that all extant Old World camelids possess functional genes for two pore-forming proteins (PRF1, GNLY) and six granzymes (GZMA, GZMB, GZMH, GZMK, GZMM, and GZMO). All these genes were represented as single copies in the genome except the GZMH gene exhibiting interspecific differences in the number of loci. High protein sequence similarities with other camelid and ungulate species were observed for GZMK and GZMM. The protein variability in dromedaries and Bactrian camels was rather low, except for GNLY and chymotrypsin-like granzymes (GZMB, GZMH).

• Klíčová slova
• NK cells, camel, cytotoxic T lymphocytes, granulysin, granzymes, perforin, ungulates,
• MeSH
• buňky NK metabolismus   MeSH
• cytotoxické proteiny tvořící póry genetika   MeSH
• cytotoxické T-lymfocyty metabolismus   MeSH
• fylogeneze MeSH
• granzymy genetika   MeSH
• perforin genetika   MeSH
• velbloudovití klasifikace   genetika   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytotoxické proteiny tvořící póry MeSH
• granzymy MeSH
• perforin MeSH

Investigating three pairs of HLA-DR (DRB1) identical unrelated persons on the induction of cytotoxic T lymphocytes (CTL) it was found that HLA-DQ antigens provided slight proliferative stimulus which was, however, sufficient for the generation of CTL. The results indicate that the HLA-DQ antigens do play a similar role in clinical bone marrow transplantation as the HLA-DR specificities.

• MeSH
• aktivace lymfocytů MeSH
• cytotoxicita imunologická MeSH
• cytotoxické T-lymfocyty imunologie   MeSH
• HLA-DQ antigeny fyziologie   MeSH
• HLA-DR antigeny imunologie   MeSH
• lidé MeSH
• test smíšené lymfocytární kultury MeSH
• testování histokompatibility MeSH
• transplantace kostní dřeně imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• HLA-DQ antigeny MeSH
• HLA-DR antigeny MeSH

Investigating HLA-A, -B, -C, -DR and -Dw antigens and MLR, CML, and PLT reactivity in two unrelated persons, it was found that, despite their HLA-D/DR identity, cytotoxic T lymphocytes (CTL) could be induced in the CML assay. The HLA-DP antigens proved to provide the proliferative impetus for the generation of CTL.

• MeSH
• buněčné dělení MeSH
• cytotoxické T-lymfocyty cytologie   imunologie   MeSH
• HLA-DP antigeny imunologie   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• HLA-DP antigeny MeSH

This review deals with cytotoxic and antiproliferative activity of fifty seven prenylated phenols isolated from Morus alba. Prenyl side chain, which can be variously modified, increases lipophilicity of the substances, thereby improving their penetration through biological membranes and thus results in an increased bioavailability. The objective was to describe the relationship between structure of the prenylated phenols and their cytotoxic effect and to clarify various mechanisms by which cytotoxic prenylated phenols induce apoptosis. The conclusions showed that the cytotoxicity of the substances increases with increasing number of the prenyl side chains and ketal groups. Conversely, modification of the prenyl side chain, such as hydroxylation, reduces cytotoxicity. The cytotoxic activity is also influenced by the presence of prenyl and hydroxyl groups at specific positions.

• Klíčová slova
• <i>Morus alba</i>, anti­proliferative activity, cytotoxicity, prenylated phenols,
• MeSH
• antitumorózní látky fytogenní izolace a purifikace   farmakologie   MeSH
• cytotoxiny izolace a purifikace   farmakologie   MeSH
• fenoly izolace a purifikace   farmakologie   MeSH
• molekulární struktura MeSH
• Morus chemie   MeSH
• prenylace MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky fytogenní MeSH
• cytotoxiny MeSH
• fenoly MeSH

Multiple myeloma has been considered a weakly immunogenic malignancy that can cause profound defects in the immune system. An important issue for the immunotherapy of myeloma is the identification of appropriate tumor-associated antigens (TAAs). Recently, hTERT (human telomerase reverse transcriptase) was detected on a majority of human malignancies. In the studies reported here, we studied antigen-specific and HLA-A2-restricted cytotoxic activity against an ARH77 myeloma cell line in vitro. An HLA-A2-specific hTERT-derived nonapeptide ((540)ILAKFLHWL(548)) was used as a TAA. Myeloma-specific cytotoxic activity of hTERT-reactive cytotoxic lymphocytes (CTLs) was established by repeated stimulation of the CTLs via dendritic cells loaded with hTERT-derived nonapeptide. These studies were able to demonstrate that hTERT-reactive T-lymphocytes can be identified and expanded using relatively simple in vitro techniques consisting of antigen-specific stimulation, immunomagnetic sorting, and then induction of rapid expansion.

• MeSH
• aktivace lymfocytů * MeSH
• antigeny nádorové imunologie   MeSH
• cytotoxické T-lymfocyty imunologie   MeSH
• dendritické buňky imunologie   MeSH
• lidé MeSH
• mnohočetný myelom imunologie   MeSH
• nádorové buněčné linie MeSH
• peptidové fragmenty genetika   imunologie   MeSH
• telomerasa genetika   imunologie   metabolismus   MeSH
• transdukce genetická MeSH
• transfekce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny nádorové MeSH
• peptidové fragmenty MeSH
• telomerasa MeSH
• telomerase reverse transcriptase (540-548) MeSH Prohlížeč
• TERT protein, human MeSH Prohlížeč

Using exhaustive chromatographic separation we have isolated (-)-tigloyl-deangeloyl-gomisin F as a novel dibenzocyclooctadiene lignan from schisandra chinensis. With the help of HPLC, we further isolated (+)-schisandrin, (+)-deoxyschisandrin, (+)-γ-schisandrin, (-)-gomisin J, (+)-gomisin A, (-)-gomisin N, (-)-tigloyl-gomisin P, (-)-wuweizisu C, (-)-gomisin D, rubrisandrin A, (-)-gomisin G, (+)-gomisin K (3) and (-)-schisantherin C. A full NMR description of (-)-schisantherin C was carried out with the aim to confirm previous reports of its structure. Compounds isolated were identified on the basis of UV, IR, (1)H- and (13)C-NMR and MS. The cytotoxicity of lignans was tested for the BY-2 cell line alone and as a synergistic effect with the cytotoxic agent camptothecin. Lignans showed various toxicity and synergistic and antagonistic effects on camptothecin-induced cytotoxicity. Cytotoxicity against colon cancer cell line LoVo was also tested.

• MeSH
• apoptóza účinky léků   MeSH
• buněčné linie MeSH
• chemická frakcionace MeSH
• cytotoxiny chemie   izolace a purifikace   toxicita   MeSH
• lidé MeSH
• lignany chemie   izolace a purifikace   toxicita   MeSH
• nádorové buněčné linie MeSH
• nukleární magnetická rezonance biomolekulární MeSH
• proliferace buněk účinky léků   MeSH
• rostlinné extrakty chemie   MeSH
• Schisandra chemie   MeSH
• tabák účinky léků   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytotoxiny MeSH
• lignany MeSH
• rostlinné extrakty MeSH

The proliferation and development of cytotoxic T cells was investigated in human peripheral blood mononuclear cell (PBMC) cultures stimulated with an antigenic extract from Candida albicans (MPPS), or with the purified protein derivative from Mycobacterium tuberculosis (PPD), or with human recombinant interleukin 2 (rIL-2). Microbial antigen- and rIL-2-induced cytotoxic T cells were able to lyse both natural killer (NK) sensitive and resistant targets. No correlation was observed between the development of T cell cytotoxicity and interferon (IFN) production in vitro. The addition of anti-class II monoclonal antibodies at the beginning of MPPS/PPD-stimulated cultures inhibited the cell proliferation, IFN production and T cell cytotoxicity, while all these cellular activities were not inhibited by anti-class II antibodies in rIL-2-stimulated cultures. Finally, antibodies to class I determinants inhibit T cell cytotoxicity, suggesting a role of such determinants in the development of the non-adaptive immunity to microbial infections.

• MeSH
• antigeny bakteriální farmakologie   MeSH
• buněčné dělení účinky léků   MeSH
• Candida albicans MeSH
• cytotoxické T-lymfocyty cytologie   účinky léků   imunologie   MeSH
• dospělí MeSH
• HLA antigeny metabolismus   farmakologie   MeSH
• interleukin-2 farmakologie   MeSH
• lidé MeSH
• monoklonální protilátky MeSH
• Mycobacterium tuberculosis MeSH
• rekombinantní proteiny farmakologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny bakteriální MeSH
• HLA antigeny MeSH
• interleukin-2 MeSH
• monoklonální protilátky MeSH
• rekombinantní proteiny MeSH

The kinase LCK and CD4/CD8 co-receptors are crucial components of the T cell antigen receptor (TCR) signaling machinery, leading to key T cell fate decisions. Despite decades of research, the roles of CD4-LCK and CD8-LCK interactions in TCR triggering in vivo remain unknown. In this study, we created animal models expressing endogenous levels of modified LCK to resolve whether and how co-receptor-bound LCK drives TCR signaling. We demonstrated that the role of LCK depends on the co-receptor to which it is bound. The CD8-bound LCK is largely dispensable for antiviral and antitumor activity of cytotoxic T cells in mice; however, it facilitates CD8+ T cell responses to suboptimal antigens in a kinase-dependent manner. By contrast, the CD4-bound LCK is required for efficient development and function of helper T cells via a kinase-independent stabilization of surface CD4. Overall, our findings reveal the role of co-receptor-bound LCK in T cell biology, show that CD4- and CD8-bound LCK drive T cell development and effector immune responses using qualitatively different mechanisms and identify the co-receptor-LCK interactions as promising targets for immunomodulation.

• MeSH
• antigeny CD4 MeSH
• antigeny CD8 metabolismus   MeSH
• cytotoxické T-lymfocyty * metabolismus   MeSH
• myši MeSH
• receptory antigenů T-buněk metabolismus   MeSH
• signální transdukce MeSH
• tyrosinkinasa p56(lck), specifická pro lymfocyty * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antigeny CD4 MeSH
• antigeny CD8 MeSH
• receptory antigenů T-buněk MeSH
• tyrosinkinasa p56(lck), specifická pro lymfocyty * MeSH

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

• Klíčová slova
• Cytotoxic T-lymphocyte antigen 4, abatacept, autoimmunity, common variable immunodeficiency, hematopoietic stem cell transplantation, hypogammaglobulinemia, immune dysregulation, primary immunodeficiency, sirolimus,
• MeSH
• antigen CTLA-4 genetika   MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• syndromy imunologické nedostatečnosti diagnostické zobrazování   genetika   terapie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigen CTLA-4 MeSH
• CTLA4 protein, human MeSH Prohlížeč