Three-dimensional segregation of supramolecular activation clusters in T cells

Monks, Colin R. F.; Freiberg, Benjamin A.; Kupfer, Hannah; Sciaky, Noah; Kupfer, Abraham

doi:10.1038/25764

Cited by 2,197 publications

(2,241 citation statements)

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“…The interaction of peptide MHC and costimulatory molecules such as CD80 (B7-1), CD54 (ICAM-1) and CD48 (LFA-3) on the APC with TCR, CD28, CD11a and CD2 on T cells forms SMACs through which proliferation, activation and response signals may flow into the T-cell. 36,37 Recently, the formation of SMACs on CD8 þ T cells was shown to occur in the presence of physiological amounts of peptide. 38 Using microscopy, we demonstrated here that these molecules were present in the synapses formed between CD8 þ effector cells and target cells expressing enhanced CD54; phosphotyrosine proteins appeared to colocalize within the synapses and increased upon enhanced expression of CD54 in target cells.…”

Section: Discussionmentioning

confidence: 99%

Amplification of the lytic potential of effector/memory CD8+ cells by vector-based enhancement of ICAM-1 (CD54) in target cells: implications for intratumoral vaccine therapy

et al. 2004

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We demonstrated that enhanced expression of the costimulatory molecules CD80, CD54 and CD48 (designated rF-TRICOM) on target cells, as delivered via a recombinant fowlpox vector, results in an increased state of stimulation of CD8 þ T cells, and consequent increased lysis of target cells. CTL studies in conjunction with antibody-blocking studies demonstrated that the enhanced effector activity of these CD8 þ T cells is mediated mainly through CD54. Intracellular staining of CD8 þ cells that interact with target cells infected with rF-TRICOM showed that they contain higher amounts of perforin and have a higher level of perforin message. Enhanced expression of costimulatory molecules (specifically CD54) on target cells using rF-TRICOM vectors also leads to the formation of stable conjugates/synapses between targets and T cells. The interaction of T cells with target cells that overexpress costimulatory molecules upon infection with rF-TRICOM leads to enhanced signaling through Lck, ZAP70, and STAT-1 in CD8 þ T cells and heightened lytic activity of CD8 þ cells through the formation of a greater number of immunological synapses. This, in turn, leads to enhanced signaling in T cells. Finally, studies were conducted in mice in which CEA is a self-antigen in an attempt to understand the potential clinical relevancy of intratumoral vaccine therapy. Mice were transplanted subcutaneously with CEA expressing tumors. Intratumoral (i.t.) vaccination was administered 8 days post tumor transplant. Mice vaccinated i.t. with rF-TRICOM demonstrated significantly reduced tumor growth and 40% of the mice had complete tumor regression. The antitumor effects were further improved by the addition of tumor antigen (CEA) in the vaccination by utilizing rF-CEA/TRICOM, with 80% of the mice experiencing complete tumor regression. These studies thus support the concept of intratumoral vaccination employing vectors expressing costimulatory molecules.

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Section: Discussionmentioning

confidence: 99%

Amplification of the lytic potential of effector/memory CD8+ cells by vector-based enhancement of ICAM-1 (CD54) in target cells: implications for intratumoral vaccine therapy

et al. 2004

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“…When an antigen presenting cell was used as a natural "ligand", however, similar results were obtained This comparison suggests that the ligand-decorated bead effectively mimics some aspects of an antigen-presenting cell. [219] Thus, a role for the CD28 co-receptor in regulating receptor proximity and immune function was implicated in studies using functionalized beads as multivalent ligands.…”

Section: 1b G-protein Coupled Receptors (Gpcrs)-gpcrsmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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Cell surface receptors acquire information from the extracellular environment and coordinate intracellular responses. Evidence from biochemical and structural studies indicates that many receptors do not operate as individual entities, but rather as part of higher-order complexes (e.g. dimers and oligomers). Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses. Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades. Despite the proposed importance of receptor-receptor processes in cellular signaling, questions concerning the mechanisms, extent, and consequences of receptor co-localization and interreceptor communication remain unanswered.Chemical synthesis can provide a variety of compounds with which to address the role of receptor assembly in signal transduction. The focus of this review is one such approach -the use of synthetic multivalent ligands to characterize receptor function. Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements. Their unique architectures imbue multivalent ligands with the ability to access binding modes not available to monovalent compounds. Multivalent ligands, therefore, are capable of illuminating aspects of inter-receptor processes that are not readily probed using conventional approaches. We suggest that, as focus shifts from investigations of the function of individual proteins and toward the analysis of multi-receptor signaling complexes, multivalent ligands will become even more valuable tools with which to ask sophisticated mechanistic questions. Further, multivalent ligands may provide new opportunities for manipulating receptor systems for the deconvolution of pathways, diagnosis, and, ultimately, the treatment of disease.

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“…Similarly, cell population expressing major histocompatibility complex (MHC) class II can be described as APCs, and natural killer (NK) cells could be characterized by killer Ig-like receptors (KIR) (1). When lymphocytes come in contact with target cells, many different molecules on APC and lymphocyte slide (like CD28/CD80 and LFA-1/ICAM-1) together and form an interface which is termed as "immunological synapse" (IS) and has been observed for T (2,3), B (4) and NK cells (5). The immunological synapse, like T cell IS, is thought to be the seat of initiation of TCR signaling events (6) which lead to different lymphocyte functions such as proliferation and cytokine production.…”

Section: Introductionmentioning

confidence: 99%