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. 2016 Sep 19;5:F1000 Faculty Rev-2344. [Version 1] doi: 10.12688/f1000research.9073.1

Figure 1. Dimensions of the interaction interfaces involving conventional αβ T-cell receptor (TCR) T cells and chimeric antigen receptor (CAR) T cells.

Figure 1.

( A) TCRs on the surface of T cells interact with peptide-major histocompatibility complex (pMHC) complexes on the surface of target cells (antigen-presenting cells). This conserved interaction spans approximately 150 Å of inter-membrane space between the two cell types. TCRs assemble in the membrane of T cells with subunits of CD3 molecules (δ, ε, γ, and ζ) and CD4 or CD8 (not shown). Proximal, intracellular molecules initiate phosphorylation of CD3 subunits and subsequent signaling pathways. Structure of the Mel5 TCR in complex with MART-1 peptide bound to HLA-A2 is shown (PDB: 3HG1) 116. ( B, C) CARs typically contain single-chain variable fragment (scFv) domains (V H and V L) of an antibody, linked to a hinge or spacer domain, transmembrane domain, and intracellular signaling domains (for example, co-stimulatory domains CD28 or 4-1BB and CD3ζ). CAR interacts with its antigen present on the target cell surface. Owing to potential differences in the size of the antigen and location of the epitope, the interaction interface of CAR-target antigen can be variable. In ( B), a representation of a CAR-target antigen interaction interface is shown by aligning the structures of an extracellular domain of the CAR target, ErbB2, in complex with the scFv of an anti-ErbB2 antibody, chA21 (PDB: 3H3B) 63, with the complete extracellular domain of ErbB2 (PDB: 1N8Z) 64. To illustrate the range of possible CAR interactions, in ( C) a representation of another CAR-target antigen interaction interface is shown for mesothelin, a membrane glycoprotein present on the cell surface of various cancers, including mesothelioma. Mesothelin was modeled by using the online tool “Phyre2” 117, followed by alignment with the domain of mesothelin that was crystallized with the Fab fragment of the anti-mesothelin monoclonal antibody MORAb-009 65, 118. Note that although these are depicted as static structures, both protein dynamics and membrane mobility will also impact interface interactions.