GZMK+ CD8 T Cells Drive Inflammaging Across Multiple Diseases
A newly identified CD8 T cell subset expressing granzyme K fuels inflammation in aging and autoimmune disease without killing cells.
Summary
Single-cell RNA sequencing has uncovered a distinct CD8 T cell subset defined by expression of granzyme K (GZMK) that accumulates in aged tissues and inflamed organs across a wide range of diseases — from rheumatoid arthritis and lupus to chronic rhinosinusitis and atherosclerosis. Unlike classical cytotoxic T cells that kill via granzyme B and perforin, GZMK+ CD8 T cells lack perforin and instead release granzyme K into the extracellular space, where it cleaves complement proteins, protease-activated receptor 1 (PAR1), and LPS — amplifying inflammatory cascades rather than destroying target cells. These cells increase with age, express exhaustion markers (PD-1, TOX, LAG3), and appear to be regulated by the transcription factor Eomes and cytokines IL-2, IL-12, and IL-15. They represent a plausible cellular link between aging immune dysfunction and chronic inflammatory disease.
Detailed Summary
The immune system's CD8 T cell compartment is far more heterogeneous than classical cytotoxic categories suggest. This 2025 mini-review in Frontiers in Immunology by Xin, Liu, Zhan, and Cao synthesizes emerging single-cell transcriptomic evidence for a functionally distinct CD8 T cell subset defined by expression of granzyme K (GZMK). The authors argue this subset represents a critical, previously underappreciated driver of chronic inflammation and inflammaging — the age-associated smoldering immune activation increasingly recognized as a root cause of multiple aging diseases.
GZMK+ CD8 T cells were first identified as conserved age-associated T cells (Taa) in murine aging tissues and subsequently confirmed to increase in human peripheral blood mononuclear cells from older individuals. Unlike terminally differentiated effector memory cells (Temra) that accumulate with age, GZMK+ CD8 T cells reside predominantly in the Tem and Tcm compartments, expressing CD27+CD28+CD57- and high CD49d — distinguishing them from both virtual memory cells and classical cytotoxic effectors. Co-inhibitory receptors PD-1, LAG3, and CTLA4 are elevated in this population alongside the exhaustion-associated transcription factor TOX, painting a picture of cells caught between effector activity and exhaustion.
The key mechanistic insight of this review is that GZMK functions very differently from granzyme B. While GzmB requires perforin-mediated cell entry to trigger caspase-dependent apoptosis, GZMK+ CD8 T cells characteristically lack perforin. Instead, granzyme K is constitutively secreted — even without TCR stimulation — and acts extracellularly. GZMK cleaves complement components C2 and C4 to generate C3 convertase, producing pro-inflammatory C3a and C5a. It also cleaves PAR1 on endothelial and immune cells, and physically disrupts LPS micelles, enhancing LPS-driven innate immune activation. TCR engagement actually suppresses GZMK expression, while cytokines IL-2, IL-12, and IL-15 strongly induce it, suggesting this subset operates through an innate-like, bystander activation mode rather than classical antigen-specific killing.
The review catalogues GZMK+ CD8 T cell enrichment across an impressive range of inflammatory conditions. In autoimmune diseases, these cells are documented in rheumatoid arthritis synovium, psoriatic skin, systemic lupus erythematosus tissue, Sjögren's disease, uveitis, IgG4-related disease, and ileal Crohn's disease. Mouse models of RA show that GZMK deficiency reduces disease severity and C3d deposition. In airway disease, clonally expanded GZMK+ CD8 T cells accumulate in nasal polyps of chronic rhinosinusitis patients, interacting with fibroblasts via the CXCR4-CXCL12 axis to drive neutrophil recruitment. TCR clonotype analysis in this setting reveals preferential recognition of Epstein-Barr virus antigens, supporting a bystander activation mechanism. The cells also appear in atherosclerotic plaques, non-alcoholic steatohepatitis, COVID-19 lung tissue, and tumors, where their pro-inflammatory activity may contribute to disease progression.
Transcriptional regulation centers on the T-box transcription factor Eomes. ATAC-seq analysis shows elevated Eomes activity in GZMK+ Tem cells versus T-bet enrichment in GZMB+ Tem cells, mirroring the T-bet/Eomes balance that governs effector versus exhausted CD8 T cell fate. Eomes has been shown to bind the GZMK promoter and directly induce expression in CD4 T cells; the authors hypothesize the aged or inflamed tissue microenvironment raises Eomes activity in CD8 T cells, generating this inflammatory subset. The review calls for future research defining exactly how environmental cues — cytokines, chronic antigen stimulation, metabolic stress — tip the Eomes/T-bet balance toward the GZMK+ fate, and whether targeting GZMK or its downstream pathways offers a viable anti-inflammaging therapeutic strategy.
Key Findings
- GZMK+ CD8 T cells increase in peripheral blood of older humans and accumulate in aged mouse tissues, characterizing them as age-associated T cells (Taa) linked to inflammaging
- These cells express CD27+CD28+CD57- with high CD49d, and are enriched in Tem/Tcm subsets — distinct from Temra and virtual memory cells that classically expand with aging
- GZMK+ CD8 T cells lack perforin; granzyme K is constitutively secreted extracellularly even without TCR stimulation, and TCR activation actually suppresses GZMK expression
- Extracellular GZMK cleaves complement C2 and C4 to form C3 convertase, generating pro-inflammatory C3a/C5a; GZMK-deficient mice showed reduced severity of rheumatoid arthritis and imiquimod-induced dermatitis with decreased C3d deposition
- In chronic rhinosinusitis with nasal polyps, clonally expanded GZMK+ CD8 T cells interact with fibroblasts via CXCR4-CXCL12, driving neutrophil chemoattractant release; TCR analysis confirmed preferential EBV-reactive clones indicating bystander activation
- IL-2/IL-12 strongly induce GZMK expression and proliferation of the subset, while IL-15 also triggers GZMK upregulation; co-inhibitory receptors PD-1, LAG3, and CTLA4 are elevated in both human and murine GZMK+ CD8 T cells
- ATAC-seq shows Eomes motif enrichment in GZMK+ Tem vs. T-bet enrichment in GZMB+ Tem cells; Eomes directly binds the GZMK promoter in CD4 T cells, suggesting a conserved transcriptional mechanism
Methodology
This is a narrative mini-review (8 pages, 103 references) synthesizing published scRNA-seq, ATAC-seq, flow cytometry, and mouse model data from multiple independent research groups. The review does not present original experimental data; findings are drawn from prior studies including murine aging models, human PBMC profiling from older vs. younger donors, and disease-specific scRNA-seq datasets spanning RA, SLE, nasal polyps, atherosclerosis, and COVID-19. Statistical values cited reflect original source publications rather than this review's own analysis.
Study Limitations
As a mini-review synthesizing heterogeneous scRNA-seq datasets, causal relationships between GZMK+ CD8 T cells and specific disease outcomes cannot be established, and findings across diseases are drawn from studies with varying methodologies, patient populations, and disease stages. Functional studies directly demonstrating GZMK-mediated pathology in humans (rather than mouse knockout models) remain limited. The authors declare funding from the National Natural Science Foundation of China and the Natural Science Foundation of Shenyang, with no stated conflicts of interest.
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