Grant: Project Grant

With age our immune system undergoes changes that are clinically important. The reduced function of one type of immune cell, T cells, is key to what is called immunosenescence: older people are vulnerable to infection and malignancies, at greater risk of developing more severe disease upon infection, and less able to respond to interventions such as vaccines. Paradoxically, the likelihood of developing an autoimmune disease, where T cells attack tissues or organs within your own body, goes up with age as well. Here we are proposing a new hypothesis that might explain why T cells may be impaired with age but at the same time more prone to unwanted responses to 'self'. Like people, T cells can 'feel' their physical environment through 'touch' sensors, responding to mechanical cues in different ways, depending on their own cell state. Our work suggests that a subset of T cells is unable to tolerate mechanical stress - dying when the physical forces they experience are too great. However, with age this T cell subset becomes more resistant to mechanical input, adapting to stiffening tissues they live in, the lymphoid organs, and possibly accruing damage to their genomic material in the process. While the greater resistance to mechanical stress may come at the cost of reduced function, it may be pivotal in allowing these T cells to gain access to tissues previously too mechanically difficult for them to survive in, accounting for the increased chance of some organ-specific autoimmune responses developing. Studying the molecular mechanisms underlying the mechano-regulation of T cell function during aging may enable us to improve immunity in older individuals without increasing autoimmune outcomes.