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

  • Immunity. 2026 Jun 9;59(6):1561-1578.e11. doi: 10.1016/j.immuni.2026.02.016.
Nancy C Allen  1 ,  Christian Ringler  2 ,  Sang Ho Woo  2 ,  Sophie Phipps  2 ,  Jin Young Lee  1 ,  Nabora Reyes  1 ,  Ritusree Biswas  1 ,  Lucile Neyton  2 ,  Andrew Willmore  2 ,  Sofia Caryotakis  3 ,  Jessica Roginsky  3 ,  Lu Guo  2 ,  Melia Magnen  4 ,  Pedro Ruivo  5 ,  Chaz Langelier  2 ,  COMET Consortium  2 ,  Mark Looney  4 ,  Averil Ma  4 ,  Vincent Auyeung  2 ,  Carolyn Calfee  2 ,  Ari B Molofsky  3 ,  Tien Peng  6
Affiliations
  • 1. Department of Medicine, San Francisco, CA, USA; Bakar Aging Research Institute, San Francisco, CA, USA.
  • 2. Department of Medicine, San Francisco, CA, USA.
  • 3. ImmunoX Initiative and Biomedical Sciences Graduate Program, San Francisco, CA, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 4. Department of Medicine, San Francisco, CA, USA; ImmunoX Initiative and Biomedical Sciences Graduate Program, San Francisco, CA, USA.
  • 5. Comparative Pathology Laboratory, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
  • 6. Department of Medicine, San Francisco, CA, USA; Bakar Aging Research Institute, San Francisco, CA, USA; ImmunoX Initiative and Biomedical Sciences Graduate Program, San Francisco, CA, USA. Electronic address: [email protected].
PMID: 41903549 DOI: 10.1016/j.immuni.2026.02.016
Abstract

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.

Keywords
ARDS; GZMK+ T cells; NF-κB; T cell exhaustion; TNFAIP3; adventitia; fibroblasts; immune aging; inflammaging; lung; tertiary lymphoid structure.
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