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

Area of Science:

• Immunology
• Cellular signaling
• Molecular mechanisms

Background:

• Gamma/delta (γδ) T cells are crucial immune cells with unique T-cell receptors (TCRs).
• The precise molecular events initiating γδ TCR signaling, known as TCR triggering, are not fully understood.
• Unlike alpha/beta TCRs, γδ TCRs lack mechanosensitivity and do not rely on co-receptors or conformational changes for activation.

Purpose of the Study:

• To elucidate the molecular mechanism of γδ TCR triggering by nonclassical MHC class Ib antigens.
• To investigate the role of cell-surface phosphatases in γδ TCR signaling.
• To identify critical steps in the activation pathway of γδ T cells.

Main Methods:

• Investigated the spatial relationship between γδ TCRs and phosphatases CD45/CD148 at synaptic contact zones.
• Utilized modified MHC class Ib ligands with altered lengths.
• Examined truncated versions of CD45 and CD148 ectodomains.
• Assessed TCR triggering and T-cell activation.

Main Results:

• γδ TCR triggering necessitates the steric segregation of CD45 and CD148 phosphatases from engaged γδ TCRs.
• Enlarging MHC class Ib ligands or truncating CD45/CD148 ectodomains impaired TCR triggering.
• Increased phosphatase access to the TCR engagement site abrogated T-cell activation.

Conclusions:

• Steric segregation of inhibitory phosphatases is a critical step in γδ TCR triggering.
• This mechanism provides insight into the signaling pathways of endogenous and synthetic tyrosine-phosphorylated immunoreceptors.
• The findings advance our understanding of unconventional T-cell activation.