Confined T cell migration controls programmed cell death 1 expression

Area of Science:

• Immunology
• Cell Biology
• Biophysics

Background:

• T cell immune checkpoint expression and dysfunction are traditionally linked solely to molecular cues.
• The role of physical forces in regulating T cell function remains underexplored.

Purpose of the Study:

• To investigate the impact of physical transmigration on T cell immune checkpoint expression.
• To elucidate the mechanisms underlying changes in T cell function due to mechanical cues.
• To explore the potential of mechanical regulation for enhancing adoptive immunotherapies.

Main Methods:

• Utilized microphysiological systems and in vivo models to simulate T cell transmigration through confined pores.
• Analyzed surface immune checkpoint markers on CD8+ T cells using proteasomal degradation assays.
• Assessed T cell fitness and function post-transmigration.
• Examined conservation of mechanisms across species and applicability to human TIL and CAR T cells.

Main Results:

• Transmigration through confined pores induced rapid, ubiquitin-mediated proteasomal degradation of programmed cell death 1 (PD-1) on CD8+ T cells within minutes.
• This mechanical process correlated with enhanced T cell fitness and function.
• The observed PD-1 loss mechanism is conserved across species and applicable to human T cells (TIL and CAR T).
• PD-1 loss was correlative with disease outcomes in human melanoma.

Conclusions:

• T cell transmigration through diverse tissue landscapes represents a form of mechanical immune regulation.
• Mechanical forces, specifically transmigration, can acutely modulate T cell immune checkpoint expression.
• This mechano-modulatory strategy holds promise for improving the quality and persistence of T cells in adoptive immunotherapy.