Background: Memory T cells are heterogeneous populations. Cytokine receptors can define different subsets of T cells with distinct functional characteristics such as expression of effector molecules and chemokine receptors. Indeed, we identified a subset of human effector memory (EM) CD8+ T cells expressing low levels of IL-7 receptor alpha chain (IL-7Rα ^low ) which produce high levels of inflammatory molecules including IFN-γ and TNF-α. Of interest, such cell subset expanded in peripheral blood of lupus patients, correlating with disease activity. However, it is largely unknown whether IL-7Rα ^low EM CD8+ T cells promote inflammation in lupus via interacting with neutrophils and monocytes which are involved in the lupus pathogenesis.

Objectives: To investigate the role of human EM CD8+ T cell subsets in promoting activation of neutrophils and monocytes with neutrophil extracellular trap (NET) formation and cytokine production in the context of lupus via IL-8 and its receptor interface.

Methods: The expression of the IL-8 receptors CXCR1 and CXCR2 by human CD8+ T cell subsets, including naive, central, and IL-7Rα ^high and ^low effector memory cells, was analyzed using flow cytometry. The effects of soluble factors, including IFN-γ and TNF-α, produced from FACS purified and activated CD8 ⁺ T cell subsets, on neutrophil extracellular trap (NET) formation and monocyte cytokine production were assessed using ELISA, flow cytometry and fluorescent microscopy. Also, anti-IFN-γ and -TNF-α were added to block these cytokines during cell culture. Acute cutaneous lupus lesions were analyzed for IL-8, IFN-γ, TNF-α, neutrophil elastase, and CD8.

Results: IL-7Rα ^low EM CD8 ⁺ T cells expressing CXCR1 and CXCR2 had increased chemotactic response to IL-8, potently induced NET formation with IL-8 and reactive oxygen species production, and promoted IL-1β production and cytokine polyfunctionality in monocytes stimulated with U1-snRNP lupus immune complex. Such effects on neutrophils and monocytes were suppressed by neutralizing IFN-γ and TNF-α produced highly from IL-7Rα ^low EM CD8+ T cells, indicating the role of these cytokines. In acute cutaneous lupus lesions, cells expressing neutrophil elastase and IL-8 were near cells expressing CD8, IFN-γ and TNF-α, supporting the possible interface of neutrophils and CD8+ T cells.

Conclusion: The results of our study demonstrate the interface of highly inflammatory human IL-7Rα ^low EM CD8 ⁺ T cells with neutrophils and monocytes in augmenting inflammation in pathologic conditions like lupus, raising the consideration of targeting such cellular interface in treating inflammation.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: None declared.