Response of Cytotoxic T Lymphocytes to Substrate Stiffness: a Nuclear Perspective

The activation of cytotoxic T lymphocytes (CTLs) in response to infection is a key feature of the adaptive immune system. Activation is triggered by the T cell receptor binding to antigenic peptide presented on antigen presenting cells (APCs). CTL activation results in extensive reorganization of the chromatin in the nucleus. The physical properties of antigen presenting cells may also contribute to CTL activation but this aspect has not been well studied. We used activating hydrogels of tunable stiffness that mimic APCs to study the impact of mechanical cues on CTL activation. We find that substrate stiffness modulates both cytoskeletal and nuclear reorganization. Confocal and super-resolution imaging showed that stiffness alters nuclear shape and levels of histone modifications associated with silenced and active chromatin regions. The temporal evolution of histone modifications and the spatial distribution of these markers are also altered by stiffness. We further examined chromatin dynamics in the nuclei of CTLs activated on surfaces of different stiffness. Our results indicate that physical and transcriptional properties of chromatin are modulated by the mechanical properties of antigen presenting surfaces. Overall, our findings suggest that CTLs integrate biochemical and physical cues to alter their chromatin organization, which is likely important for the induction of appropriate gene expression programs required to mount a robust immune response.