scholarly journals Precise T cell recognition programs designed by transcriptionally linking multiple receptors

Science ◽  
2020 ◽  
Vol 370 (6520) ◽  
pp. 1099-1104 ◽  
Author(s):  
Jasper Z. Williams ◽  
Greg M. Allen ◽  
Devan Shah ◽  
Igal S. Sterin ◽  
Ki H. Kim ◽  
...  
Keyword(s):  
Molecular Recognition ◽  
Cellular Level ◽  
Target Cells ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
Notch Receptors ◽  
Multiple Receptors ◽  
Engineered T Cells ◽  
Intracellular Antigen

Living cells often identify their correct partner or target cells by integrating information from multiple receptors, achieving levels of recognition that are difficult to obtain with individual molecular interactions. In this study, we engineered a diverse library of multireceptor cell-cell recognition circuits by using synthetic Notch receptors to transcriptionally interconnect multiple molecular recognition events. These synthetic circuits allow engineered T cells to integrate extra- and intracellular antigen recognition, are robust to heterogeneity, and achieve precise recognition by integrating up to three different antigens with positive or negative logic. A three-antigen AND gate composed of three sequentially linked receptors shows selectivity in vivo, clearing three-antigen tumors while ignoring related two-antigen tumors. Daisy-chaining multiple molecular recognition events together in synthetic circuits provides a powerful way to engineer cellular-level recognition.

scholarly journals Cell-mediated lympholysis to H-2-matched target cells modified with a series of nitrophenyl compounds.

1976 ◽  
Vol 144 (4) ◽  
pp. 1134-1140 ◽  
Author(s):  
T G Rehn ◽  
J K Inman ◽  
G M Shearer
Keyword(s):  
T Cell ◽  
Target Cells ◽  
Cell Recognition ◽  
Receptor Model ◽  
Spleen Cells ◽  
Effector Cells ◽  
T Cell Recognition ◽  
Cytotoxic Effector

The specificity of C57BL/10 cytotoxic effector cells generated by in vitro sensitization with autologous spleen cells modified with a series of related nitrophenyl compounds was investigated. The failure of trinitrophenyl (TNP)-sensitized effector cells to lyse TNP-beta-alanylglycylglycyl(AGG)-modified target cells is presented as evidence contradicting the intimacy or dual receptor model or T-cell recognition in its simplest form. Data are also shown indicating that sensitization with N-(3-nitro-4-hydroxy-5-iodophenylacetyl)-AGG-modified stimulating cells generates noncross-reacting clones of cytotoxic effector cells.

scholarly journals In Vivo Tumor Targeting by the B-Subunit of Shiga Toxin

2008 ◽  
Vol 7 (6) ◽  
pp. 7290.2008.00022 ◽  
Author(s):  
Thomas Viel ◽  
Estelle Dransart ◽  
Fariba Nemati ◽  
Emilie Henry ◽  
Benoit Thézé ◽  
...  
Keyword(s):  
Shiga Toxin ◽  
Renal Excretion ◽  
Cellular Level ◽  
Target Cells ◽  
B Subunit ◽  
Monocytes And Macrophages ◽  
Intestinal Pathogen ◽  
Tumoral Cells ◽  
Tumor Area

Delivery of drugs to the appropriate target cells would improve efficacy and reduce potential side effects. The nontoxic B-subunit of the intestinal pathogen-produced Shiga toxin (STxB) binds specifically to the glycosphingolipid Gb3, overex-pressed in membranes of certain tumor cells, and enters these cells through the retrograde pathway. Therefore, STxB binding to Gb3 receptors may be useful for cell-specific vectorization or imaging purposes. Here we labeled STxB with a fluorophore to evaluate its potential as an in vivo cell-specific targeting reagent in two different models of human colorectal carcinoma. Fluorescent STxB was administered systemically to xenografted nude mice, and its biodistribution was studied by optical imaging. The use of fluorescent STxB allowed the combination of the macroscopic observations with analyses at the cellular level using confocal microscopy. After administration, the fluorescent STxB was slowly eliminated by renal excretion. However, it accumulated in the tumor area. Furthermore, STxB was demonstrated to enter the Gb3-expressing tumoral cells, as well as the epithelial cells of the neovascularization and the monocytes and macrophages surrounding the xenografts.

T cell recognition of antigen in vivo: Role of the H-2 complex

1980 ◽  
Vol 3 (2) ◽  
pp. 213-245 ◽  
Author(s):  
J. Sprent ◽  
R. Korngold ◽  
K. Molnar-Kimber
Keyword(s):  
T Cell ◽  
Cell Recognition ◽  
T Cell Recognition

scholarly journals Enhancement in Specific CD8+ T Cell Recognition of EphA2+ Tumors In Vitro and In Vivo after Treatment with Ligand Agonists

2008 ◽  
Vol 181 (11) ◽  
pp. 7721-7727 ◽  
Author(s):  
Amy K. Wesa ◽  
Christopher J. Herrem ◽  
Maja Mandic ◽  
Jennifer L. Taylor ◽  
Cecilia Vasquez ◽  
...  
Keyword(s):  
T Cell ◽  
Cd8 T Cell ◽  
Cell Recognition ◽  
T Cell Recognition

Stomatogastric Nervous System

2017 ◽  
Author(s):  
Wolfgang Stein
Keyword(s):  
Nervous System ◽  
Neural Circuit ◽  
Activity Patterns ◽  
Cellular Level ◽  
Target Cells ◽  
Descending Pathways ◽  
Stomatogastric Nervous System ◽  
Motor Circuits ◽  
Insight Into

The crustacean stomatogastric nervous system contains a set of distinct but interacting rhythmic motor circuits that control movements of the foregut. When isolated, these circuits produce activity patterns that are almost perfect replicas of their behavior in vivo. The ease with which distinct circuit neurons are identified, recorded, and manipulated has provided considerable insight into the general principles of how motor circuits operate and are controlled at the cellular level. The small number of relatively large neurons has facilitated several technical advances in neuroscience research and allowed the identification of one of the earliest circuit connectomes. This enabled, for the first time, studies of circuit dynamics using the relationships between all component neurons of a nervous center. A major discovery was that circuits are not dedicated to producing a single neuronal activity pattern, and that the involved neurons are not committed to particular circuits. This flexibility results predominantly from the ability of neuromodulators to change the cellular and synaptic properties of circuit neurons. The relatively unique access to, and detailed documentation of, identified circuit, sensory, and descending pathways has also started new avenues into examining how individual modulatory neurons and transmitters affect their target cells. Groundbreaking experimental and modeling work has further demonstrated that the intrinsic properties of neurons depend on their recent history of activation and that neurons and circuits counterbalance destabilizing influences by compensatory homeostatic regulation of ionic conductances. The stomatogastric microcircuits continue to provide key insight into neural circuit operation in numerically larger and less accessible systems.

scholarly journals Cellular and genetic control of antibody responses. V. Helper T-cell recognition of H-2 determinants on accessory cells but not B cells.

1979 ◽  
Vol 149 (5) ◽  
pp. 1208-1226 ◽  
Author(s):  
A Singer ◽  
K S Hathcock ◽  
R J Hodes
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Helper T Cells ◽  
Cell Recognition ◽  
Helper T Cell ◽  
T Cell Recognition ◽  
Accessory Cells

Requirements for helper T-cell recognition of H-2 determinants expressed on adherent accessory cells and on B cells was individually assessed in the anti-hapten PFC responses to TNP-KLH. Complicating allogeneic effects were minimized or avoided by the use of helper T cells from normal F1 hybrids, parent leads to F1 chimeras, and F1 leads to parent chimeras. The results of both in vitro and in vivo experiments demonstrated that: (a) helper T cells are not required to recognize the identical H-2 determinants on both accessory cells and B cells; (b) helper T cells are required to recognize K or I-A region-encoded determinants expressed on accessory cells; (c) no requirement was observed in vitro or in vivo for helper T-cell recognition of B-cell-expressed H-2 determinants; and (d) no requirement was observed for H-2 homology between accessory cells and B cells. The absence of required helper T-cell recognition of the identical H-2 determinants on both accessory cells and B cells was demonstrated in two ways: (a) naive of KLH-primed (A x B)F1 hybrid helper T cells collaborated equally well with B cells from either parentA or parentB in the presence of accessory cells from either parent; (b) A leads to (A x B)F1 chimeric spleen cells depleted of accessory cells collaborated equally well with accessory cells from either parentA or parentB, even though the B cells only expressed the H-2 determinants of parentA. A requirement for helper T-cell recognition of K or I-A region-encoded H-2 determinants on accessory cells was also demonstrated in two ways: (a) (A x B)F1 leads to parentA chimeric spleen cells depleted of accessory cells collaborated with accessory cells from parentA but not parentB; and (b) (A x B)F1 leads to parentA chimeric helper T cells collaborated with normal F1 B cells only in the presence of parental or recombinant accessory cells that expressed the K or I-A region-encoded determinants of parentA. Although restricted in their ability to recognize H-2 determinants on accessory cells, it was demonstrated both in vitro and in vivo that (A x B)F1 leads to parentA chimeric helper T cells were able to collaborate with B cells from either parentA or parentB. In vitro in the presence of accessory cells from parentA, (A x B)F1 leads to parentA chimeric helper T cells collaborated equally well with B cells from either parent. In addition, the inability of (A x B)F1 leads to parentA chimeric helper T cells to collaborate with (B + accessory) cells from parentB was successfully reversed by the addition of parentA SAC as added accessory cells. In vivo, upon the addition of parentA accessory cells, (A x B)F1 leads to parentA chimeric helper T cells collaborated with parentB B cells in short-term adoptive transfer experiments.

T cell recognition of a tumor-associated glycoprotein and its synthetic carbohydrate epitopes: stimulation of anticancer T cell immunity in vivo

1987 ◽  
Vol 25 (3) ◽  
Author(s):  
CarinaM. Henningsson ◽  
Subnaicker Selvaraj ◽  
GrantD. MacLean ◽  
MavanurR. Suresh ◽  
AntoineA. Noujaim ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Immunity ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
Carbohydrate Epitopes ◽  
Cell Immunity ◽  
Synthetic Carbohydrate ◽  
Stimulation Of

scholarly journals T-Cell Recognition of the HspX Protein of Mycobacterium tuberculosis Correlates with Latent M. tuberculosis Infection but Not with M. bovis BCG Vaccination

2007 ◽  
Vol 75 (6) ◽  
pp. 2914-2921 ◽  
Author(s):  
Annemieke Geluk ◽  
May Young Lin ◽  
Krista E. van Meijgaarden ◽  
Eliane M. S. Leyten ◽  
Kees L. M. C. Franken ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
T Cell Responses ◽  
Cell Recognition ◽  
T Cell Epitopes ◽  
Bcg Vaccination ◽  
T Cell Recognition ◽  
Cell Responses

ABSTRACT During stationary growth or in vitro conditions mimicking relevant aspects of latency, the HspX protein (Rv2031c) is specifically upregulated by Mycobacterium tuberculosis. In this study we compared T-cell responses against HspX and the secreted M. tuberculosis protein Ag85B (Rv1886c) in tuberculosis (TB) patients, tuberculin skin test-positive individuals, M. bovis BCG-vaccinated individuals, and healthy negative controls. Gamma interferon responses to HspX were significantly higher in M. tuberculosis-exposed individuals than in M. tuberculosis-unexposed BCG vaccinees. In contrast, no such differences were found with respect to T-cell responses against Ag85B. Therefore, BCG-based vaccines containing relevant fragments of HspX may induce improved responses against this TB latency antigen. To identify relevant major histocompatibility complex class I- and class II-restricted HspX-specific T-cell epitopes, we immunized HLA-A2/Kb and HLA-DR3.Ab0 transgenic (tg) mice with HspX. Two new T-cell epitopes were identified, p91-105 and p31-50, restricted via HLA-A*0201 and HLA-DRB1*0301, respectively. These epitopes were recognized by human T cells as well, underlining the relevance of HspX T-cell recognition both in vivo and in vitro. In line with the data in humans, BCG immunization of both tg strains did not lead to T-cell responses against HspX-derived epitopes, whereas nonlatency antigens were efficiently recognized. These data support the notion that BCG vaccination per se does not induce T-cell responses against the latency antigen, HspX. Thus, we suggest that subunit vaccines incorporating HspX and/or other latency antigens, as well as recombinant BCG strains expressing latency antigens need to be considered as new vaccines against TB.

scholarly journals In Vivo siRNA Delivery to Immunosuppressive Liver Macrophages by α-Mannosyl-Functionalized Cationic Nanohydrogel Particles

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1905 ◽  
Author(s):  
Leonard Kaps ◽  
Nadine Leber ◽  
Adrian Klefenz ◽  
Niklas Choteschovsky ◽  
Rudolf Zentel ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Near Infrared ◽  
Infrared Imaging ◽  
Sirna Delivery ◽  
Mannose Receptor ◽  
Cellular Level ◽  
Immune Defense ◽  
Target Cells

Macrophages are the front soldiers of the innate immune system and are vital for immune defense, tumor surveillance, and tissue homeostasis. In chronic diseases, including cancer and liver fibrosis, macrophages can be forced into an immunosuppressive and profibrotic M2 phenotype. M2-type macrophages overexpress the mannose receptor CD206. Targeting these cells via CD206 and macrophage repolarization towards an immune stimulating and antifibrotic M1 phenotype through RNA interference represents an appealing therapeutic approach. We designed nanohydrogel particles equipped with mannose residues on the surface (ManNP) that delivered siRNA more efficiently to M2 polarized macrophages compared to their untargeted counterparts (NonNP) in vitro. The ManNP were then assessed for their in vivo targeting potential in mice with experimental liver fibrosis that is characterized by increased profibrotic (and immunosuppressive) M2-type macrophages. Double-labelled siRNA-loaded ManNP carrying two different near infrared labels for siRNA and ManNP showed good biocompatibility and robust uptake in fibrotic livers as assessed by in vivo near infrared imaging. siRNA–ManNP were highly colocalized with CD206+ M2-type macrophages on a cellular level, while untargeted NP (NonNP) showed little colocalization and were non-specifically taken up by other liver cells. ManNP did not induce hepatic inflammation or kidney dysfunction, as demonstrated by serological analysis. In conclusion, α-mannosyl-functionalized ManNP direct NP towards M2-type macrophages in diseased livers and prevent unspecific uptake in non-target cells. ManNP are promising vehicles for siRNA and other drugs for immunomodulatory treatment of liver fibrosis and liver cancer.

Sign in / Sign up

Export Citation Format

Share Document