Persistent Interleukin-18 Fuels Expansion of CD38⁺HLA-DR⁺CD8⁺ T Cells in Still Disease and Macrophage Activation...

Still disease (SD) is an autoinflammatory disorder characterized by remarkably high interleukin-18 (IL-18) levels. Increasing evidence suggests that adaptive immunity also contributes to its pathogenesis, particularly in refractory courses. Macrophage activation syndrome (MAS), one of SD's most severe complications, is associated with further IL-18 elevation and expansion of CD38⁺HLA-DR⁺CD8⁺ T cells. However, whether and when this population emerges during SD remains unknown. We therefore examined CD38⁺HLA-DR⁺CD8⁺ T cells across disease stages.

CD38⁺HLA-DR⁺CD8⁺ T cells were analyzed longitudinally: at SD onset (therapy-naive; n = 19), during clinically inactive disease (n = 15), and before or at MAS occurrence (n = 12). Spectral flow cytometry and bulk RNA sequencing were performed. Correlations with clinical and laboratory parameters were assessed. In vitro cytokine stimulations of healthy donor (HD)-derived peripheral blood mononuclear cells and CD8⁺ lymphocytes were performed to explore mechanisms driving differentiation of these cells.

CD38⁺HLA-DR⁺CD8⁺ T cells were expanded from SD onset and peaked in MAS (median: 4.61% and 31.7%, respectively, versus 0.87% in HDs). Transcriptomic profiling of these cells revealed enrichment of activation, cytotoxicity, and proliferation programs, which were confirmed at the protein level. Frequencies correlated with markers of systemic inflammation, T cell activation, and serum IL-18 levels. Sustained IL-18 stimulation in vitro induced robust and persistent expansion of CD38⁺HLA-DR⁺CD8⁺ cells, recapitulating key ex vivo phenotypic features.

CD38⁺HLA-DR⁺CD8⁺ cells, previously primarily associated with MAS, are detectable early in SD. Persistent IL-18 exposure promotes their expansion. These findings identify CD38⁺HLA-DR⁺CD8⁺ T cells as a potential mechanistic link between SD and MAS and highlight this subset as a candidate therapeutic target.