Frequency of HLA-DR+CD38hi T cells identifies and quantifies T-cell activation in hemophagocytic lymphohistiocytosis, hyperinflammation, and immune regulatory disorders

Abstract

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. 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. Results for sIL-2R, CXCL9, and ferritin assays were obtained from patient's medical records. Frequency of HLA-DR+CD38high(hi) T-cells was assessed in different T-cell subsets using flow cytometry. 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+CD38hi T cells in CD8+ T (r= 0.65, P< .0001) and CD4+ T (r= 0.77; P< .0001) effector memory (TEM) 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+ TEM and CD8+ TEM activation with sIL-2R levels; thus, attesting its utility in initial diagnosis and in evaluating treatment response. The frequency of HLA-DR+CD38hi T-cells in the CD8+ TEM compartment also correlated with plasma CXCL9 (r= 0.42; P= .0120) and ferritin levels (r= 0.32; P=.0037). This study demonstrates that flow cytometry-based direct T-cell activation assessed by HLA-DR+CD38hi Tcells accurately quantifies T-cell activation and stronglycorrelates with sIL-2R levels across a spectrum ofhyperinflammatory and immune dysregulation disorders.