Frequency of HLA-DR⁺CD38^hi T cells identifies and quantifies T-cell activation in hemophagocytic lymphohistiocytosis, hyperinflammation, and immune regulatory disorders

Background: Quantifying T-cell activation is essential for the diagnosis and evaluation of treatment response in various hyperinflammatory and immune regulatory disorders, including hemophagocytic lymphohistiocytosis. Plasma soluble IL-2 receptor (sIL-2R) is a well-established biomarker for evaluating systemic T-cell activation. However, the limited availability of sIL-2R testing could result in delayed diagnosis. Furthermore, high sIL-2R levels may not always reflect T-cell activation.

Objectives: To address these limitations, this study investigated whether cell surface markers of T-cell activation, HLA-DR, and CD38, as assessed by flow cytometry, could be used to quantify systemic T-cell activation in a variety of inflammatory disease states and examine its correlation with sIL-2R levels.

Methods: Results for sIL-2R, CXCL9, and ferritin assays were obtained from patient's medical records. Frequency of HLA-DR⁺CD38^high(hi) T-cells was assessed in different T-cell subsets using flow cytometry.

Results: In this study's cohort, activation in total CD8⁺ T (r = 0.65; P < .0001) and CD4⁺ (r = 0.42; P < .0001) T-cell subsets significantly correlated with plasma sIL-2R levels. At the disease onset, the frequency of HLA-DR⁺CD38^hi T cells in CD8⁺ T (r = 0.65, P < .0001) and CD4⁺ T (r = 0.77; P < .0001) effector memory (T_EM) compartments correlated strongly with sIL-2R levels. Evaluation of T-cell activation markers in follow-up samples also revealed a positive correlation for both CD4⁺ T_EM and CD8⁺ T_EM activation with sIL-2R levels; thus, attesting its utility in initial diagnosis and in evaluating treatment response. The frequency of HLA-DR⁺CD38^hi T-cells in the CD8⁺ T_EM compartment also correlated with plasma CXCL9 (r = 0.42; P = .0120) and ferritin levels (r = 0.32; P = .0037).

Conclusions: This study demonstrates that flow cytometry-based direct T-cell activation assessed by HLA-DR⁺CD38^hi T cells accurately quantifies T-cell activation and strongly correlates with sIL-2R levels across a spectrum of hyperinflammatory and immune dysregulation disorders.