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WIREs Nanomed Nanobiotechnol
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Investigative and clinical applications of synthetic immune synapses

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The immune synapse (IS) has emerged as a compelling model of cell–cell communication. This interface between a T cell and antigen‐presenting cell (APC) serves as a key point in coordinating the immune response. A distinguishing feature of this interface is that juxtacrine signaling molecules form complex patterns that are defined at micrometer and submicrometer scales. Moreover, these patterns are highly dynamic. While cellular and molecular approaches have provided insight into the influence of these patterns on cell–cell signaling, replacing the APC with a synthetic, micro/nanoengineered surface promises a new level of sophistication to these studies. Micropatterning of multiple ligands onto a surface, for example, allowed the direct demonstration that T cells can sense and respond to microscale geometry of the IS. Supported lipid bilayers have captured the lateral mobility of natural ligands, allowing insight into this complex property of the cell–cell interface in model systems. Finally, engineered surfaces have allowed the study of forces and mechanosensing in T cell activation, an emerging area of immune cell research. In addition to providing new insight into biophysical principles, investigations into IS function may allow control over ex vivo T cell expansion. Bioreactors based on these concepts may find immediate application in enhancing cellular‐based immunotherapy. WIREs Nanomed Nanobiotechnol 2013, 5:75–85. doi: 10.1002/wnan.1195

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Figure 1.

Basic components of an immune synapse (IS). (a) T cell activation begins with engagement of the T cell receptor (TCR) with a peptide‐loaded major histocompatibility complex (pMHC). (b) TCR–pMHC, CD28‐CD86/CD80, and LFA‐1‐ICAM‐1 form a core set of molecules defining the IS. (c) Signaling complexes are organized into distinct patterns within the IS, which are dependent on the specific T cell–antigen‐presenting cell interaction. Red dots represent TCR‐containing microclusters, whereas the blue dots represent LFA‐1, which coalesce into the larger blue areas in the stable synapses. Comparisons between the stable synapse structures are made in the main text.

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Figure 2.

Capturing the spatial complexity of the immune synapse (IS). (a) Micropatterned surfaces allow arbitrary control over the layout of an artificial IS. A variety of these techniques allow patterning of biomolecules onto the substrate. The small red, green, and blue shapes in this and subsequent panels correspond to ligands to T cell receptor (TCR), CD28, and LFA‐1, respectively, as was set forth in Figure 1(b). (b) Preactivated T cells respond to the geometry of TCR–LFA‐1 signaling. (Reprinted with permission from Ref 31. Copyright 2004 National Academy of Sciences U.S.A.) (c) Naïve T cells respond to the geometry of a tricomponent surface containing patterns of TCR and CD28 ligands, separated and surrounded by ICAM‐1. (Reprinted with permission from Ref 32. Copyright 2008 National Academy of Sciences U.S.A.) The shaded outlines in panels b and c illustrate the size of a typical T cell on these surfaces. (d) The supported lipid bilayer system provides natural mobility to antigen‐presenting cell proteins presented on a substrate. (e) Micropatterning and nanopatterning of the bilayer system capture the influence of cytoskeletal structures on membrane protein dynamics.

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Figure 3.

Mechanical forces in T cell activation. (a) Activation of T cells by anti‐CD3 and anti‐CD28 attached onto polyacrylamide gels. (b) Activation of naïve mouse CD4+ T cells correlates with increasing gel rigidity, E. *P < 0.05, **P < 0.005 compared to 200 kPa surface. Data are mean ± SD, n = 7. (Reprinted with permission from Ref 51. Copyright 2012 Rockefeller University Press) (c) Localization of active (phosphorylated) signaling proteins Zap70 and pan‐SFK as a function of gel rigidity. Cells were fixed and stained for these proteins 30 min after initiation of cell–substrate contact. (Reprinted with permission from Ref 51. Copyright 2012 Rockefeller University Press)

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Figure 4.

Topology of the immune synapse. (a) Scanning electron micrograph of a human CD4+ T cell interacting with a K562 antigen‐presenting cell. (b) These cells separated during processing, allowing clearer visualization of the cell–cell interface. Source: Dr. Manus Biggs, Columbia University.

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James F. Leary

James F. Leary
has been contributing to nanomedical research and technologies throughout his career. Such contributions include the invention of high-speed flow cytometry, cell sorting techniques, and rare-event methods. Dr. Leary’s current research spans across three general areas in nanomedicine. The first is the development of high-throughput single-cell flow cytometry and cell sorting technologies. The second explores BioMEMS technologies. These include miniaturized cell sorters, portable devices for detection of microbial pathogens in food and water, and artificial human “organ-on-a-chip” technologies which consists of developing cell culture chips capable of simulating the activities and mechanics of entire organs and organ systems. His third area of research aims at developing smart nano-engineered systems for single-cell drug or gene delivery for nanomedicine. Dr. Leary currently holds nine issued U.S. Patents with four currently pending, and he has received NIH funding for over 25 years.

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