NF-κB-activated fibroblasts orchestrate inflammaging and emergence of pro-inflammatory granzyme K⁺ T cells

While inflammaging supposedly drives some of the most common diseases affecting the elderly, little is known about the tissue drivers of inflammaging. In this study, we demonstrate that age-dependent activation of nuclear factor κB (NF-κB) in tissue fibroblasts remodeled the immune architecture, promoting the emergence of an exhausted granzyme K (GZMK)⁺CD8⁺ T cell population recently identified in normal aging as well as autoimmunity and cancer. Fibroblast-specific NF-κB activation triggered a fibroblast-macrophage-T cell circuit to form tertiary lymphoid structures in the lung and promoted the emergence of exhausted GZMK⁺ T cells that were different from those emerging in chronic viral infection. Fibroblastic activation of NF-κB increased host susceptibility to acute lung injury and mimicked severe pneumonia commonly seen in elderly patients, which was alleviated by depletion of GZMK⁺ T cells. Our data provide a structural basis for inflammaging, where fibroblasts orchestrate the complex immune aging phenotype in non-immune tissues, increasing susceptibility to age-related diseases.