Insights into the initiation of TCR signaling

Abstract

The initiation of T cell antigen receptor signaling is a key step that can result in T cell activation and the orchestration of an adaptive immune response. Early events in T cell receptor signaling can distinguish between agonist and endogenous ligands with exquisite selectivity, and show extraordinary sensitivity to minute numbers of agonists in a sea of endogenous ligands. We review our current knowledge of models and crucial molecules that aim to provide a mechanistic explanation for these observations. Building on current understanding and a discussion of unresolved issues, we propose a molecular model for initiation of T cell receptor signaling that may serve as a useful guide for future studies.

Figure 1

Schematic depiction of kinetic proofreading. Models of TCR binding and kinetic proofreading. (a) A model where TCR binds to two different ligands. The complexes thus formed can lead to downstream signaling with rate k_p. The agonist and endogenous ligands bind to TCR with different on- and off-rates (k_on^Ag, k_off^Ag, k_on^En, k_off^En). Ag, agonist; En, endogenous; p^AgMHC, agonist peptide–MHC; p^EnMHC, endogenous peptide–MHC. (b) A model that includes kinetic proofreading. Following TCR binding to peptide–MHC (pMHC), a series of biochemical transformations must occur to form intermediates (C₀, C₁ and so on) before product downstream signaling can occur. Each modification can be reversed completely, with rate k₁. This series of biochemical modifications must be driven out of equilibrium by ATP consumption.

Figure 2

Schematic representation of the mechanosensor model of TCR signal initiation. After TCR binds to the ligand, the crawling of the T cell on the APC results in a force that imparts a torque on the TCR, thus positioning the TCR-CD3 complex in the architecture necessary for signaling to ensue. This schematic depicts how torque can cause a conformational change or reorientation of the TCR to help facilitate downstream signaling.

Figure 3

The regulation of Lck by phosphorylation. Shown are the four states of phosphorylation described in this review, based on phosphorylation of Tyr394 in the activation loop of the catalytic domain and of Tyr505 in the negative regulatory segment. Also shown are the molecules thought to regulate the transition between the different phosphorylation states.

Figure 4

TCR activation as a consequence of the combined relocalization of CD4 and CD8 coreceptors and bound Lck. In the basal state, the ζ-chain ITAMs are phosphorylated (red dots) and bound to autoinhibited Zap70. Lck initiates activation by phosphorylating Zap70 Tyr319 in interdomain B, relieving Zap70 autoinhibition and creating a binding site for the Lck SH2 domain, further stabilizing the activated state of Lck and, thereby, initiating a positive feedback loop in which Lck can promote further local phosphorylation events. Zap70 trans-autophosphorylation of its activation loop results in its catalytic activation.