Ligand-induced segregation from large cell-surface phosphatases is a critical step in γδ TCR triggering

Area of Science:

• Immunology
• Cellular Signaling
• T Cell Biology

Background:

• Gamma/delta (γδ) T cells are unique lymphocytes recognizing diverse ligands via γδ T cell receptors (TCRs).
• The precise molecular mechanisms initiating γδ TCR signaling, or TCR triggering, remain largely unknown.
• Unlike alpha/beta TCRs, γδ TCRs lack mechanosensitivity and coreceptor dependence for triggering.

Approach:

• Investigated the role of cell-surface phosphatases CD45 and CD148 in γδ TCR triggering.
• Examined the impact of steric segregation of phosphatases from engaged TCRs at synaptic junctions.
• Manipulated MHC class Ib ligand length and phosphatase ectodomain size to alter phosphatase access to TCRs.

Key Points:

• γδ TCR triggering by MHC class Ib antigens necessitates steric exclusion of CD45 and CD148 phosphatases from engaged TCRs.
• Synaptic close contact zones are critical for this phosphatase segregation.
• Elongating MHC ligands or truncating phosphatase ectodomains inhibits TCR triggering and T cell activation by preventing segregation.

Conclusions:

• Identified steric segregation of inhibitory phosphatases as a key step in γδ TCR triggering.
• Provides novel insights into the fundamental mechanism of γδ T cell activation.
• Offers a framework for understanding endogenous and synthetic immunoreceptor signaling.