Macrophage-mediated bystander T cell activation in varicose veins

Background

Up to one-third of all adults are affected by chronic venous insufficiency, with varicose veins being a common manifestation of the condition. It is believed that inflammation plays a central role in the progression of the disease; however, the immune cell populations and mechanisms involved remain unclear.

Methods

Varicose veins were subjected to a stepwise mechanical and enzymatic dissociation, and the mononuclear cells resulting from these steps were characterized by flow cytometry. CD206-negative connective tissue macrophages and CD206-positive venous wall macrophages were sorted from five donors and subjected to transcriptomic profiling. Cytokine production by T cells in varicose veins was characterized following inhibition of intracellular protein transport. The ability of cytokines identified in macrophage transcriptomes to induce cytokine production in CD8 ⁺ and CD4 ⁺ effector and memory T cells was investigated using combinations of recombinant cytokines.

Results

Varicose veins harbor CD206 ^neg IL-1α ⁺ S100A8/9 ⁺ macrophages in the connective tissue and pro-resolving and tissue regenerating CD206 ⁺ TIMD4 ⁺ LYVE1 ⁺ macrophages in the vein wall. T cells predominantly localize within the connective tissue, express an effector-memory T cell phenotype and produce IFN-γ in situ. Cytokines identified in the macrophage transcriptome collectively induced IFN-γ, as well as TNF-α, IL-22, and GM-CSF in effector memory T cells; in addition to IL-15 and IL-18, TNF-α and IL-10 proved to be key drivers.

Conclusions

The identified macrophage-T cell cytokine axis contributes to chronic venous insufficiency pathogenesis and represents a potential therapeutic target.

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