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
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).
- 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
Allogeneic cancer cell lines serve as universal source of tumor-associated antigens in cancer vaccines. Immunogenic high hydrostatic pressure-killed cancer cells derived from cell lines can be used for the generation of dendritic cell (DC)-based active cellular immunotherapy of non-small cell lung cancer (NSCLC). We investigated the expression of 12 known NSCLC tumor-associated antigens (TAA) (CEA, MAGE-A1, MAGE-A3, MAGE-A4, PRAME, hTERT, HER2, MUC1, Survivin, STEAP1, SOX2 and NY-ESO-1) in 6 NSCLC cell lines as candidates for the generation of DC-based lung cancer vaccine. We showed that the selected antigenic profile of these cell lines overlaps to various degrees with that of primary NSCLC tumors (n = 52), indicating that 4 out of 6 NSCLC cell lines would be suitable for DC-based vaccine generation. We further investigated the presence of TAA-specific T cells in blood of NSCLC patients (n = 32) using commercially available peptide mixes in an in vitro stimulation assay. IFN-γ+CD8+ and IFN-γ+CD4+ T cell responses to all antigens were detected in NSCLC patients. Interestingly, despite higher TAA expression in squamous cell carcinoma (SCC) the responsiveness of patients' T cells to stimulation was significantly lower in SCC patients than in adenocarcinoma (AC) patients. This suggests qualitative differences in T cell functionality between NSCLC subtypes. Based on this study, and in order to maximize the amount of treatable patients, we selected a mix of H520 and H522 NSCLC cell lines for DC-based vaccine preparation. We also established a minimal panel of antigenic peptide mixes (CEA, hTERT, PRAME, HER2) for immunomonitoring of T cell responses during the DC-based lung cancer immunotherapy in Phase I lung cancer clinical trial (NCT02470468).
- MeSH
- antigenní specifita receptorů T-buněk * MeSH
- antigeny nádorové imunologie MeSH
- cytotoxické T-lymfocyty imunologie metabolismus MeSH
- dendritické buňky imunologie metabolismus MeSH
- imunoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory plic imunologie metabolismus patologie terapie MeSH
- nemalobuněčný karcinom plic imunologie metabolismus patologie terapie MeSH
- protinádorové vakcíny MeSH
- senioři MeSH
- staging nádorů MeSH
- T-lymfocyty imunologie metabolismus MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: In a prospective study with long-term follow-up, we analyzed circulating T cell subsets in patients with metastatic colorectal cancer (mCRC) in the context of primary tumor sidedness, KRAS status, and clinical outcome. Our primary goal was to investigate whether baseline levels of circulating T cell subsets serve as a potential biomarker of clinical outcome of mCRC patients treated with an anti-VEGF-based regimen. METHODS: The study group consisted of 36 patients with colorectal adenocarcinoma who started first-line chemotherapy with bevacizumab for metastatic disease. We quantified T cell subsets including Tregs and CD8+ T cells in the peripheral blood prior to therapy initiation. Clinical outcome was evaluated as progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). RESULTS: 1) mCRC patients with KRAS wt tumors had higher proportions of circulating CD8+ cytotoxic T cells among all T cells but also higher measures of T regulatory (Treg) cells such as absolute count and a higher proportion of Tregs in the CD4+ subset. 2) A low proportion of circulating Tregs among CD4+ cells, and a high CD8:Treg ratio at initiation of VEGF-targeting therapy, were associated with favorable clinical outcome. 3) In a subset of patients with primarily right-sided mCRC, superior PFS and OS were observed when the CD8:Treg ratio was high. CONCLUSIONS: The baseline level of circulating immune cells predicts clinical outcome of 1st-line treatment with the anti-VEGF angio/immunomodulatory agent bevacizumab. Circulating immune biomarkers, namely the CD8:Treg ratio, identified patients in the right-sided mCRC subgroup with favorable outcome following treatment with 1st-line anti-VEGF treatment.
- MeSH
- adenokarcinom krev farmakoterapie mortalita patologie MeSH
- bevacizumab aplikace a dávkování terapeutické užití MeSH
- cytotoxické T-lymfocyty metabolismus MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- inhibitory angiogeneze aplikace a dávkování terapeutické užití MeSH
- kolorektální nádory krev farmakoterapie mortalita patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů farmakoterapie MeSH
- míra přežití MeSH
- nádorové biomarkery metabolismus MeSH
- následné studie MeSH
- počet lymfocytů MeSH
- prospektivní studie MeSH
- protoonkogenní proteiny p21(ras) analýza MeSH
- regulační T-lymfocyty metabolismus MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- vaskulární endoteliální růstový faktor A antagonisté a inhibitory MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Pri tepelnej úprave potravín vznikajú spontánne reakciou sacharidov, oxidovaných lipidov alebo vitamínu C s bielkovinami látky nazývané produkty Maillardovej reakcie (Maillard reaction products, MRP). Nakoľko priemyselná výroba dojčenských formúl vyžaduje tepelnú sterilizáciu, dojčenské formuly obsahujú v porovnaní s materským mliekom vysoké koncentrácie MRP. Ich nadmerný alimentárny prívod môže indukovať u zdravých dospelých, ale najmä u pacientov s diabetom či renálnou insuficienciou biologické účinky, ako napr. zvýšenie zápalových markerov, ukazovateľov oxidačného poškodenia, nefrotoxické a diabetogénne účinky, priberanie na hmotnosti, ktoré môžu viesť k prehĺbeniu alebo rozvoju obezity, aterosklerózy, nefropatie či diabetu. Prvé výsledky signalizujú, že vysoký príjem MRP v umelej strave dojčiat je spojený s vyššou záťažou detského organizmu týmito potenciálne škodlivými látkami. Tieto údaje poukazujú na nové skutočnosti vysvetľujúce všeobecne známu a jednoznačnú fyziologickú nadradenosť materského mlieka nad umelou výživou dojčiat.
During food-processing under high temperatures, sugars, oxidized lipids and vitamin C spontaneously form with proteins substances called Maillard reaction products (MRPs). Industrial processing of artificial infant formulas (IF) requires heat-sterilization. Thus, content of MRPs in IF is much higher than in the human mother milk. Excessive intake of MRPs from thermally processed foods may exert biological effects in patients with diabetes or renal insufficiency, but also in healthy adults, e.g. increase of inflammatory markers and markers of oxidative damage, nephrotoxic and diabetogenic effects, weight gain, and thus may participate in the development or aggravation of obesity, atherosclerosis, nephropathy and diabetes. In infants, the high intake of MRPs in consumed artificial infant formulas represents a burden of potentially noxious substances. These results point at a new mechanism explaining the well-known physiological dominance of human breast milk over the artificial infant formula.
- MeSH
- cytotoxické T-lymfocyty metabolismus MeSH
- financování organizované MeSH
- kojenec MeSH
- lidé MeSH
- Maillardova reakce MeSH
- manipulace s potravinami metody MeSH
- mateřské mléko metabolismus MeSH
- náhražky mateřského mléka metabolismus MeSH
- potrava pro kojence škodlivé účinky využití MeSH
- potravinářský průmysl metody MeSH
- produkty pokročilé glykace metabolismus škodlivé účinky MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH