NF-κB-activated fibroblasts orchestrate inflammaging and emergence of pro-inflammatory granzyme K+ T cells - PubMed (original) (raw)

. 2026 Mar 27:S1074-7613(26)00086-5.

doi: 10.1016/j.immuni.2026.02.016. Online ahead of print.

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

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

Nancy C Allen et al. Immunity. 2026.

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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Conflict of interest statement

Declaration of interests N.C.A. and T.P. have filed a patent on the targeting of GZMK(+) T cells in lung diseases.

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