Fig. 2

Schematic summarizing the recent studies on CD38⁺ HLA-DR⁺ cycling lymphocytes in HLH / MAS. [8,9,10,11] HLH / MAS is associated with a prominent expansion of CD38⁺HLA-DR⁺CD8⁺ T cells and milder increase of CD4⁺ T lymphocytes and NK cells with similar characteristics. CD38⁺HLA-DR⁺ cycling T cells are highly proliferative and metabolically active based on transcriptomic analysis and they are also prolific producers of IFN-γ, perforin and granzymes. The expansion of these cells correlates with clinical laboratory findings seen in patients with HLH/MAS. IL-15 and IFN-I in combination can induce the differentiation of CD38⁺HLA-DR⁺ lymphocytes in vitro [11]. Other cytokines including IL-2, IL-12, and IL-18 may elicit synergist effects on IFN-γ production. EBV infection can also induce the expansion of CD38⁺HLA-DR⁺ T cells with or without MAS [50, 51].