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Review
. 2015 Apr;1853(4):781-90.
doi: 10.1016/j.bbamcr.2014.09.001. Epub 2014 Sep 6.

Linking form to function: Biophysical aspects of artificial antigen presenting cell design

Karlo Perica  1 , Alyssa K Kosmides  1 , Jonathan P Schneck  2
Affiliations
Review

Linking form to function: Biophysical aspects of artificial antigen presenting cell design

Karlo Perica et al. Biochim Biophys Acta. 2015 Apr.

Abstract

Artificial antigen presenting cells (aAPCs) are engineered platforms for T cell activation and expansion, synthesized by coupling T cell activating proteins to the surface of cell lines or biocompatible particles. They can serve both as model systems to study the basic aspects of T cell signaling and translationally as novel approaches for either active or adoptive immunotherapy. Historically, these reductionist systems have not been designed to mimic the temporally and spatially complex interactions observed during endogenous T cell-APC contact, which include receptor organization at both micro- and nanoscales and dynamic changes in cell and membrane morphologies. Here, we review how particle size and shape, as well as heterogenous distribution of T cell activating proteins on the particle surface, are critical aspects of aAPC design. In doing so, we demonstrate how insights derived from endogenous T cell activation can be applied to optimize aAPC, and in turn how aAPC platforms can be used to better understand endogenous T cell stimulation. This article is part of a Special Issue entitled: Nanoscale membrane organisation and signalling.

Keywords: Artificial antigen presenting cell; Immunotherapy; Microparticle; Microscale interaction; Nanoscale interaction.

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Figures

Figure 1
Figure 1. The Signal 1+2 Paradigm
Endogenous APC present two necessary and sufficient signals for T cell activation. Signal 1 is cognate peptide presented in the context of MHC, whereas Signal 2 comprises numerous activating and inhibitory co-stimulatory ligands that bind receptors on T cells. aAPC are synthesized by coupling either specific MHC-peptide complexes or polyclonally activating anti-CD3 antibody as Signal 1, and either activating antibodies against co-stimulatory molecules such as CD28 or recombinant co-stimulatory molecules such as B7.1 (rB7.1).
Figure 2
Figure 2. Scales of Organization
T cell membrane organization at several scales contributes to signaling and activation. TCR are pre-clustered in 15–30 nm nanoclusters prior to T cell activation, particularly on the surface of previously activated or memory cells. Upon MHC binding, 35–70 nm signaling nanoclusters form that drive downstream signaling. These clusters migrate to the center of the T cell-APC contact site, forming the cSMAC, and are subsequently internalized and degraded. Adhesion molecules such as LFA-1 are distributed in the pSMAC, which together with the cSMAC forms the micron-scale immune synapse.
Figure 3
Figure 3. Scales of Organization
A. Studies from patterned lipid bilayers suggest that T cells preferentially activate against surfaces with MHC-peptide (purple) forming the center of the contact site, and anti-CD28 (orange) distributed in the periphery. In contrast, most aAPC are synthesized with uncontrolled protein distribution B. Ellipsoid rather than spherical micro-aAPC provide a greater surface area and decreased surface curvature for optimal T cell engagement, leading to enhanced antigen-specific T cell activation and proliferation. C. Nanoscale aAPC, less than 100 nm in diameter, have recently been shown to be capable of activating T cells. These nano-aAPC (orange) can “sense” nanoscale TCR distribution, as they preferentially bind to activated T cells which have more clustered TCR (purple) than naive cells. This leads to higher avidity for aAPC binding, but fewer aAPC bound to each T cell, since each aAPC binds multiple TCR. This effect enhanced activation of activated cells by nano-aAPC, whereas this preference was not observed with micro-aAPC.
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