Losing Their Grip: Aging Weakens Treg TCR Catch Bonds Under Force 2260253

Abstract Introduction Aging is associated with a decline in regulatory T cell (Treg) function contributing to the increased severity of autoimmune disease in older individuals. Our data indicate that Tregs from middle-aged mice display reduced suppressive function in experimental autoimmune encephalomyelitis (EAE). In aged mice we found diminished force-dependent suppression via trogocytosis of peptide:MHC complexes. These functional decreases correlated with a reduction in the bond lifetime under force in aged mice compared to their young counterparts. This data suggests that age-related biophysical changes in TCR binding kinetics drive the impaired function of Tregs. To test this, we examined the bond lifetime under force in myelin oligodendrocyte glycoprotein (MOG) specific Tregs in aged C57BL/6 and NOD mice. We found a reduction in bond lifetime under force in aged Tregs. We hypothesized the reduction in bond lifetime was due to changes in membrane rigidity and our findings demonstrate that aged Tregs exhibit increased rigidity. This alters membrane dynamics and reduces the stability of TCR:pMHC interactions, decreasing the capacity for aged Tregs to perform force mediated suppression via trogocytosis. In addition we show this lowers antigen specific Treg function and leads to earlier EAE onset and increased severity. Together these studies are the first to show how aging alters Treg TCR:pMHC binding kinetics and will allow for exploration of therapeutic strategies to enhance immune tolerance in older individuals with autoimmune disease. Methods Results Conclusion Funding Source 5R01AI169835-03 Topic Categories Basic Autoimmunity (BA)