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Basics of Allergy
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Rafeul Alam, Dipa K Sheth, Magdalena M Gorska
Mature DC present antigenic epitopes to a specific T cell through the formation of the ‘immunological synapse’ (Dustin 2002). TCR and co-stimulatory molecules (e.g., CD4/CD8, CD28) engage with their counter ligands on APCs in the immunological synapse. The TCR is associated with the CD3 complex (composed of a, b, g, d, e and two z subunits). Proper assembly of this receptor complex is important for TCR signaling. The lack of the CD3g subunit causes severe immunodeficiency whereas that of the CD3e subunit induces a milder form of immunodeficiency. The binding of the TCR to the peptide-MHC complex results in the activation of CD4- and CD3-associated tyrosine kinases—Lck: lymphocyte specific kinase and Src: Rouse sarcoma. These kinases phosphorylate CD3-associated z chains at ITAM (immunoreceptor tyrosine-based activation motif) sites, which allow docking of multiple signaling molecules and transduction of signals through downstream pathways (Hermiston et al. 2002).
Cell-mediated immunity
Published in Gabriel Virella, Medical Immunology, 2019
José C. Crispín, Gabriel Virella
The intracellular portion of the TCR heterodimer is very short and lacks signal transduction capacity. However, the TCR is associated with a complex of molecules that transmit its signal when it recognizes an antigen on an APC. This molecular complex consists of four proteins (CD3γ, δ, ε, and ζ) equipped with immunoreceptor tyrosine-based activation motifs (ITAMs) that contain tyrosine residues (two per ITAM) that become phosphorylated by tyrosine kinases. This represents the initial intracellular event triggered by T-cell antigen recognition.
Fc Receptors
Published in Maurizio Zanetti, J. Donald Capra, The Antibodies, 1999
An intracytoplasmic activation motif, shared by receptors involved in the direct (BCR), MHC-mediated (TCR) or antibody-mediated (FcR) recognition of antigen was understood to account for the cell-triggering ability of FcR (Figure 3). ITAMs were found in the transduction subunits that are associated with BCR (Igα and 1gβ), with TCR (TCRζ, CD3γ, CD3δ and CD3ɛ) and with FcR (FcRβ and FcRγ) [3]. In some T cells, FcRγ replaces TCRζ in the TCR complex [215]. Conversely, in human NK cells, TCRζ may replace FcRγ in FcγRIIIA [88]. ITAMs are composed of a twice repeated YxxL motif, separated by 6–8 variable residues. An ITAM is also present in the intracytoplasmic domain of the human single-chain FcγRIIA and FcγRIIC. This ITAM has a longer intervening sequence (12 residues) between the two YxxL than other ITAMs [3].
Human Mesenchymal glioblastomas are characterized by an increased immune cell presence compared to Proneural and Classical tumors
Published in OncoImmunology, 2019
Ioannis Kaffes, Frank Szulzewsky, Zhihong Chen, Cameron J. Herting, Ben Gabanic, José E. Velázquez Vega, Jennifer Shelton, Jeffrey M. Switchenko, James L. Ross, Leon F. McSwain, Jason T. Huse, Bengt Westermark, Sven Nelander, Karin Forsberg-Nilsson, Lene Uhrbom, Naga Prathyusha Maturi, Patrick. J. Cimino, Eric C. Holland, Helmut Kettenmann, Cameron W. Brennan, Daniel J. Brat, Dolores Hambardzumyan
In PN GBM, AIF1 was the only gene to have an impact on survival. High AIF1 levels were associated with a significantly worse prognosis in patients with PN tumors compared to those PN GBM with low expression (median survival high AIF1: 7.80 months, low AIF1: 10.56 months) (Supplementary Fig. S1). Conversely, in MES GBM, high expression of AIF1 conferred a survival benefit, with median survival lengths in the high-AIF1 cohort being almost twice as long (high AIF1: 14.36 months, low AIF1: 7.31 months) (Figure 2(a)). In the MES subtype, high expression of the T cell marker CD3G was also prognostically beneficial (median survival high CD3G: 14.36 months, low CD3G: 10.43 months) (Supplementary Fig. S2). No significant survival differences were observed in CL tumors (Supplementary Fig. S3).
Efficient tumor killing and minimal cytokine release with novel T-cell agonist bispecific antibodies
Published in mAbs, 2019
Nathan D. Trinklein, Duy Pham, Ute Schellenberger, Ben Buelow, Andrew Boudreau, Priya Choudhry, Starlynn C. Clarke, Kevin Dang, Katherine E. Harris, Suhasini Iyer, Brett Jorgensen, Payal P. Pratap, Udaya S. Rangaswamy, Harshad S. Ugamraj, Omid Vafa, Arun P. Wiita, Wim van Schooten, Roland Buelow, Shelley Force Aldred
Human CD3δε and CD3γε heterodimers were expressed in ExpiCHO cells (ThermoFisher). Plasmids encoding CD3δ or CD3γ extracellular domains fused to mouse IgG1 Fc domains were co-transfected with the CD3ε mouse IgG1 Fc-fusion construct to express the respective heterodimer. C-terminal polyhistidine (His) tags on CD3δ and CD3γ were used for binding and imidazole-gradient elution of heterodimers from Ni-Sepharose XL (GE Healthcare). His-tagged human CD3ε was purchased from Creative Biomart (#CD3E-213H). Antigen-antibody binding kinetics analysis was performed on the Octet QK-384 (ForteBio). Briefly, HIS1K sensors were used to immobilize His-tagged CD3δε and CD3γε molecules. For interactions with CD3ε, the CD3ε antigen was in solution and the antibodies were immobilized using anti-human IgG Fc capture sensors (new antibodies on human Fc) or using anti-mouse IgG Fc capture sensors (OKT3 on mouse Fc). After baseline readings, sensors were dipped into antibody solutions (7-points, 2-fold dilution series). Association and dissociation were measured for 180 and 240 seconds, respectively. Data analysis was performed with Octet Data Analysis v11.0 HT (ForteBio), using a standard 1:1 binding model. Note that bivalent antibodies bind to the immobilized proteins with avidity, preventing the measurement of true kinetic rates.
MUC16 mutations improve patients’ prognosis by enhancing the infiltration and antitumor immunity of cytotoxic T lymphocytes in the endometrial cancer microenvironment
Published in OncoImmunology, 2018
T cell, CD8+ T cell, NK cell and CD56dim NK cell signatures were built by a research group, using genes specific for these immune cells.24 T cell signature genes include PRKCQ, CD3D, CD3G, CD28, LCK, TRAT1, BCL11B, CD2, ITM2A, SH2D1A, CD6, CD96, NCALD, GIMAP5, CD3E and SKAP1. CD8+ T cell signature genes include CD8B, CD8A, PF4, SF1, LIME1, PRR5, GZMM, SLC16A7, SRSF7, APBA2, HAUS3, LEPROTL1, GADD45A, ZFP36L2, KAT6A, ZEB1, ZNF609, MAPKAPK5-AS1, THUMPD1, VAMP2, ZNF91, ZNF22, TMC6, DNAJB1, FLT3LG, CDKN2AIP, TSC22D3, TBCC, RBM3, ABT1, TMEM259, CAMLG, PPP1R2, AES, KLF9 and PRF1. NK cell signature genes include GAGE2, ZNF747, XCL1, XCL2, GNAS, SLC30A5, SGMS1, MCM3AP, TBXA2R, CDC5L, FGF18, MRC2, PSMD4, PRX, ZNF205, APBB2, ZNF528, MAPRE3, BCL2, KANK2, ATL2, SPN, FZR1, PDLIM4, TRPV6, LDB3, ADARB1, PPP4R3A, TCTN2, TINAGL1, IGFBP5, ALDH1B1, FUT5 and NCR1. CD56dim NK cell signature genes include SPON2, GZMB, TTC38, PMEPA1, IL21R, GTF3C1, S1PR5, KIR3DL2, KIR2DL3, KIR3DL1, KIR3DL3.