T cell immunoengineering with advanced biomaterials

Abstract

Recent advances in biomaterials design offer the potential to actively control immune cell activation and behaviour. Many human diseases, such as infections, cancer, and autoimmune disorders, are partly mediated by inappropriate or insufficient activation of the immune system. T cells play a central role in the host immune response to these diseases, and so constitute a promising cell type for manipulation. In vivo, T cells are stimulated by antigen presenting cells (APC), therefore to design immunoengineering biomaterials that control T cell behaviour, artificial interfaces that mimic the natural APC-T cell interaction are required. This review draws together research in the design and fabrication of such biomaterial interfaces, and highlights efforts to elucidate key parameters in T cell activation, such as substrate mechanical properties and spatial organization of receptors, illustrating how they can be manipulated by bioengineering approaches to alter T cell function.

Fig. 1. Schematic of T cell interactions. (A) T cells experience a range of stimuli in vivo that can be broadly classified into biochemical and physical cues. (B) The TCR/CD3 complex is central to T cell activation, requiring engagement of peptide-bearing MHC (pMHC) with the TCR/CD3 complex, CD4 on the T cell surface with pMHC on the APC cell surface, and stimulation through CD28 binding to CD80/CD86.

Fig. 2. Schematic of T cell stimulation and 2D biomaterials interfaces controlling TCR movement. (A) Schematic of a single TCR/CD3 complex (B) a schematic of hypothetical micro-cluster formation; individual TCR/CD3 complexes associate to form nano-domains, which pre-exist on the T cell surface. On engagement with APC, TCR/CD3 micro-clusters form (C) a schematic of activation, where TCR/CD3 micro-clusters move from the periphery to a central Super Molecular Activation Cluster (c-SMAC), and become surrounded by rings of costimulatory and adhesion molecules. (D) Using chromium barriers on fluid lipid bilayers restricts micro-cluster formation and so synapse structure (E) nanopatterns fabricated using block copolymer micellar lithography present anchoring surfaces for TCR/CD3 ligands with precise inter-ligand spacing (scale bar 100 nm) such surfaces show dramatic differences in their ability to activate T cells. This may be due to bound nanoclusters being spaced too far apart on surfaces with large inter-ligand density, with nanoclusters unable to concatenate if pinned to static nanoparticles, preventing TCR/CD3 micro-cluster formation and so signalling, shown schematically (altered from ref. 39). Copyright: (D) adapted from ref. 46 Mossman et al., Science, 2005, 310(5751), 1191–1193. Reprinted with permission from AAAS; (E) adapted with permission from ref. 39 Delcassian et al. Nano Lett., 2013, 13(11), 5608–5614, Copyright 2013 American Chemical Society.

Fig. 3. Dynamic T cell interfaces with APC-mimicking biomaterials. (A) Biodegradable PLGA particles have been used to deliver surface bound and soluble T cell signals, paracrine IL2 delivery seems to result in increased activation. (B) A schematic of paramagnetic nanoparticles functionalized with anti-CD3 and anti-CD28, which represent the move towards dynamic biomaterials that are able to induce T cell activation in response to specific stimuli. Copyright: (B) adapted with permission from ref. 51 Perica et al. ACS Nano, 2014, 8(3), 2252–2260, Copyright 2014 American Chemical Society.

Derfogail Delcassian

Susanne Sattler

Iain E. Dunlop