POS1392 HIGHLY INFLAMMATORY IL-7 RECEPTOR ALPHA LOW EFFECTOR MEMORY CD8+ T CELLS PROMOTE NEUTROPHIL EXTRACELLULAR TRAPS AND LUPUS IMMUNE COMPLEX-MEDIATED MONOCYTE ACTIVATION IN HUMANS
Authors: I. Kang, M. S. Shin, J. Yoo, H. J. Park, X. Dong
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> 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<sup>low</sup>) 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<sup>low</sup> EM CD8+ T cells promote inflammation in lupus via interacting with neutrophils and monocytes which are involved in the lupus pathogenesis. <h3>Objectives:</h3> 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. <h3>Methods:</h3> The expression of the IL-8 receptors CXCR1 and CXCR2 by human CD8+ T cell subsets, including naive, central, and IL-7Rα<sup>high</sup> and <sup>low</sup> 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<sup>+</sup> 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. <h3>Results:</h3> IL-7Rα<sup>low</sup> EM CD8<sup>+</sup> 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<sup>low</sup> 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. <h3>Conclusion:</h3> The results of our study demonstrate the interface of highly inflammatory human IL-7Rα<sup>low</sup> EM CD8<sup>+</sup> 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. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>