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Professor Marco Fritzsche from the Kennedy Institute, Oxford and Professor Karsten Kruse from the University of Geneva, provide a theoretical perspective on how the mechanical forces between a T cell and an antigen-presenting cell (APC) can influence the interaction between a single T cell receptor (TCR) and its target molecule, the peptide-major histocompatibility complex (pMHC).
In the immune system, T cells play a crucial role in defending the body against infection and disease. When a T cell encounters an antigen-presenting cell (APC) displaying a foreign peptide, it must quickly determine whether that peptide is from a harmful, foreign source or a harmless, self-source. This self-nonself discrimination is essential for activating an appropriate immune response.
Emerging research suggests that the mechanical forces between a T cell and an APC during their initial interaction may help T cells make this critical determination.
‘Mechanical force has repeatedly been highlighted to be involved in T cell activation, but its biological significance has remained under active consideration,’ said Marco. ‘Our theoretical analysis suggests that the lifetime of TCR-pMHC bonds, and thus the degree of their phosphorylation which is essential for T cell activation, depends considerably on the TCR rigidity and the average magnitude and frequency of an applied oscillatory force.’
Published in Proceedings of the National Academy of Sciences (PNAS), their theoretical analysis found that the number of total TCR phosphorylation events, which determines whether a T cell becomes activated, can increase by several orders of magnitude when a constant force in the range of a few piconewtons (pN) is applied to a TCR-pMHC bond that exhibits "catch bond" behaviour, where the bond lifetime is enhanced by the applied force.
The team also explain that fluctuations in the applied force, as might occur due to dynamic cell protrusions like microvilli during early T cell activation, can partially compensate for applying a non-optimal average force. They also demonstrated that the ability of T cells to rebind the pMHC after the initial TCR-pMHC bond breaks can strongly affect the total number of TCR phosphorylation events, particularly for catch bonds.
The findings suggest that mechanical forces may be exploited by T cells to improve their ability to discriminate between self and non-self molecules, which is crucial for effective immune responses and the prevention of autoimmune diseases.
‘Our theoretical analysis indicates that mechanical force is an important factor in early T cell activation that warrants further experimental investigation,’ concluded Marco. ‘Demonstrating the role of mechanical forces in T cell biology could lead to new therapeutic opportunities for modulating the immune response.’