Figure 3.

The Safety On model of the T cell receptor (TCR) triggering. (A) In resting T cells, the TCR complex (yellow) is prevented from spontaneously signaling by electrostatic interactions between basic-rich sequences in the cytoplasmic domains of CD3ε and CD3ζ and negatively charged phospholipids (colored red). This interaction buries critical tyrosine residues within immunotyrosine-based activation motifs (ITAMs) of CD3ε and CD3ζ in the hydrophobic core of the membrane, thus physically sequestering them from Lck (green), preventing phosphorylation and initiation of downstream signaling. When the TCR engages cognate peptide presented on major histocompatibility complex (pMHC, purple), CD3 tails are released from the membrane through an unknown mechanism, allowing them to become phosphorylated by Lck and initiate downstream signaling. (B) A null hypothesis for the “Safety On” model which is also consistent with current data. CD3 cytoplasmic tails are in dynamic equilibrium between being buried in and free of the membrane. Agonist pMHC-induced recruitment of Lck, and/or segregation of phosphatases [see van der Merwe and Dushek (55) for review of alternate triggering mechanisms], allows phosphorylation of CD3 chains, which prevents re-association with the membrane. (C) Local release of Ca²⁺ (blue circles), downstream of initial activation (first panel), may also play a role by neutralizing negatively charged lipids by releasing CD3 tails in nearby unligated TCRs and allowing them to become phosphorylated (second and third panels). This may be important for amplifying initial signaling events.