TCR Signaling Emerges from the Sum of Many Parts

Abstract

"How does T cell receptor signaling begin?" Answering this question requires an understanding of how the parts of the molecular machinery that mediates this process fit and work together. Ultimately this molecular architecture must (i) trigger the relay of information from the TCR-pMHC interface to the signaling substrates of the CD3 molecules and (ii) bring the kinases that modify these substrates in close proximity to interact, initiate, and sustain signaling. In this contribution we will discuss advances of the last decade that have increased our understanding of the complex machinery and interactions that underlie this type of signaling.

Keywords: CD3; TCR; co-receptor; complex; multi-molecular machinery; triggering.

Figure 1

The architecture of the TCR-CD3 complex. (A) The αβTCR is shown (PDB: 1TCR) as a surface rendered structure with the variable (V) regions on top and the constant (C) regions on the bottom. The constant region surfaces discussed herein are colored: Cα AB loop (green), Cα C strand (yellow), Cα DE loop (cyan) Cα F strand (red), Cβ CC′ loop (orange), and Cβ FG loop (pink). (B) A top down view of the transmembrane domains, with red and blue dots indicating the acidic and basic transmembrane charge residues (respectively) that mediate assembly of the complex (Call et al., ; Kuhns and Davis, ; Kuhns et al., 2010). (C) A front-on view of the extracellular (ECD), transmembrane helices (TM), and intracellular (ICD) domains according to our current interpretation of the existing data. The subunits are color coded as labeled: TCRα (white), TCRβ (magenta), CD3γ (orange), CD3δ (cyan), CD3ε (marine).

Figure 2

The multi-molecular T cell signaling machinery. Shown is the state of the field as we understand it regarding the multi-molecular higher-order assemblies that mediate sustained TCR signaling on CD4⁺ (left) and CD8⁺ (right) T cells (Garcia et al., , ; Sun et al., , ; Wang et al., , ; Call et al., ; Arnett et al., ; Kjer-Nielsen et al., ; Kuhns and Davis, ; Kuhns et al., 2010).

Figure 3

The water cooler model of TCR triggering. (A) Cartoons of a “classic-style” water cooler in action. The valve is closed on the left and water is retained in the tank. Once the lever is pushed down it pivots over its rigid base (right), causing an upward pull on the attached valve. This opposing action opens the valve and allows water to flow from the tank. (B) An analogous mechanism may trigger the flow of pMHC-specific information from the outside to the inside of a T cell. A cartoon of the basic triggering components is shown, similarly to Figures 1 and 2. The unengaged TCR-CD3 complex on the left is relatively upright. Upon ligand engagement (right), the TCR pivots over the rigid CD3 heterodimers at its base, possibly pushing them into the membrane while pulling up on the CD3ζζ on the opposite side of the complex.