CD8 T-cell activation as a key measure in various forms of HLH, including MAS. When CD8 T cells are activated by encounter with cognate antigens, they divide and differentiate. Some cell surface markers, including high levels of CD38, HLA-DR, and low levels of CD4, have been demonstrated in humans to signify recent antigenic activation. Although this process is a normal part of T-cell responses, experimental models of HLH demonstrate that CD8 T-cell activation is greatly heightened and drives disease pathogenesis. Similarly, patients with familial HLH display distinctive and high levels of recently activated CD8 T cells. De Matteis et al have now extended this finding to patients with MAS and other secondary HLH and identify dim CD4 expression as correlating with MAS severity.