Flotillin-2 dampens T cell antigen-sensitivity and functionality.

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• T cell receptor (TCR) engagement is crucial for T cell activation, but the precise regulatory mechanisms at the plasma membrane are not fully understood.
• Understanding how TCR signaling thresholds are modulated is key to developing effective immunotherapies.

Approach:

• Investigated the role of the membrane scaffolding protein Flotillin-2 (Flot2) in regulating T cell activation.
• Utilized T cell-specific Flot2-deficient mice and performed analyses including single-cell RNA sequencing and super-resolution microscopy.
• Assessed T cell effector functions, signaling pathways (e.g., ZAP70 and LCK phosphorylation), and T cell receptor (TCR) clustering.

Key Points:

• Flotillin-2 (Flot2) deletion in T cells significantly increases antigen sensitivity and enhances TCR signaling and effector functions upon weak stimulation.
• Flot2-deficient mice showed reduced tumor growth and improved immunity against infections.
• Flot2 ablation leads to increased surface TCR nanocluster formation, suggesting a role in modulating TCR clustering and thus T cell activation thresholds.

Conclusions:

• Flotillin-2 (Flot2) acts as a negative regulator of T cell activation sensitivity by influencing TCR clustering at the plasma membrane.
• Modulating Flot2 levels could be a therapeutic strategy to enhance T cell reactivity in conditions like cancer and chronic infections.
• These findings provide new insights into the molecular regulation of T cell activation and its implications for immune-mediated diseases.