PDE4 inhibitor mitigates activated CD8+ T cells through NF-κB signaling in Behçet's syndrome.

OBJECTIVES

Behçet's disease (BD) is a systemic vasculitis with inflammatory lesions mediated by cytotoxic T cells and neutrophils. Here, we explore the critical involvement of NF-κB signaling pathway in proinflammatory CD8+ T cells differentiation and disease progress of BD patients.

METHODS

We performed microarray gene expression analyses, flow cytometry, immunophenotyping, immunohistochemistry and functional assessments of CD8+ T cells from BD patients and HD.

RESULTS

Transcriptionally, among the 6,595 up-regulated genes in CD8+ T cells of BD vs HD, we highlighted a great enrichment for pathways linked to NF-κB and TLR signaling (i.e. NFKB1, RELB, REL, TLR1, IRF4). Phenotypically, CD8+ T cells from BD had a higher expression of phosphorylated NF-κB (pNF-κB, 4.4 ± 0.9 vs. 1.8 ± 0.2 in MFI, p = 0.001), were more activated (higher CD11c, CD11b, CD25 and TNF-α, IFN-γ expression) and exhibited more expression of Perforin and Granzyme B (33% ± 9 vs. 9 ± 5, p = 0.009, 47% ± 8 vs.21% ± 6, p = 0.02, respectively) as compared to HD. Phosphodiesterase-4 (PDE4), an immune cell enzyme that activate the NF-κB pathway was up-regulated in blood and skin lesions of BD. In vitro and in vivo inhibition of PDE4 strongly inhibited CD8+ T cell activation, cytokine secretion, cytotoxicity and proliferation.

CONCLUSION

We highlighted that activated CD8+ T cells through NF-κB signaling pathway are instrumental in BD.