Remote force application to the T cell receptor modulates CD4\(^+\) T cell activation

Clarke, Joseph (2023). Remote force application to the T cell receptor modulates CD4\(^+\) T cell activation. University of Birmingham. Ph.D.

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Abstract

Whilst T cell receptor (TCR) signalling pathways become increasingly well understood, the precise mechanism by which TCR triggering is achieved remains elusive. Models of TCR triggering surrounding TCR aggregation or segregation from inhibitory phosphatases have provided compelling insight, but these models have their limitations and fail to fully address how the TCR is able to trigger upon recognition of cognate antigen. Recent studies propose that the TCR is able to function as a mechanosensor, whereby it can directly interpret the mechanical cues it encounters and translate these into internal biochemical signals. However, whilst these studies are mechanistically revealing, they fail to address if force application to the TCR can achieve robust T cell activation and modulate T cell phenotype.

Here, we utilise small magnetic nanoparticles (MNPs, 0.25-1μm diameter) functionalised with anti-CD3 antibodies to transfer forces to the TCR in the presence of external dynamic magnetic fields. We show that force application to the TCR increases TCR signal strength to reach the thresholds required for T cell activation. We find that these thresholds are reached through force mediated membrane remodelling of the TCR complex and subsequent accumulation of downstream signalling intermediates. Interestingly, force application to MNPs functionalised with higher levels of antibody, which provide a higher TCR signal strength in the absence of force, dampened T cell activation and induced co- inhibitory receptor expression, suggestive of additional negative feedback thresholds set higher than thresholds for T cell activation.

The data presented in this thesis thus supports a concept whereby force application to the TCR promotes TCR signalling, membrane TCR remodelling and has further consequences on downstream CD4\(^+\) T cell activation.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):