Organ-scale control of persistent, host-destructive T cell responses following infection 2256259

Abstract Introduction The mammalian immune system deploys potent inflammatory responses to defend host tissues from invading pathogens, but these responses also damage the very tissues they evolved to protect. This challenge is exemplified by the influenza-infected lung, where organ-scale tissue damage threatens lung physiology. T cells play a dual role in this process: they are critical for clearing infected cells, yet they also release diffusible inflammatory mediators that drive off-target tissue damage. We investigated how these T cell responses are regulated at the organ scale to balance pathogen clearance against protecting tissue integrity. Methods We combined high-resolution multiplexed and optically cleared 3D volumetric imaging with antibody-mediated perturbations to dissect the spatiotemporal control of T cell responses, tissue damage, and repair during sublethal influenza infection. Results We found that damaged lung regions exhibited intense T cell accumulation that persisted even as the epithelium repaired post-viral clearance. Strikingly, despite their potential to exacerbate injury, these T cells were surrounded by widespread up-regulation of PD-L1 spanning millimeters of damaged and regenerating tissue. Temporally controlled blockade of PD-1—PD-L1 interactions locally reactivated effector T cell functions within these regions and markedly disrupted epithelial repair. Together, these results reveal that PD-L1 induction protects the lung from T cell—mediated damage post-infection, and they reveal a spatially coordinated, organ-scale mechanism that restrains inflammation to enable tissue recovery. Conclusion Our results demonstrate that even after viral clearance, residual effector T cells threaten tissue integrity, necessitating organ-scale, PD-L1—mediated inhibition to preserve lung structure and function. These findings highlight a fundamental principle of immune regulation: tissue recovery depends not only on resolving inflammation over time, but also on spatially containing it across the organ. Funding Source This material is based upon work supported by a National Science Foundation Graduate Research Fellowship under award number 2141064; by the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM087237; Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)