Bulk RNA-Seq, scRNA-Seq, and mass cytometry studies together established (a) the presence of both IFN-I and IFN-γ signatures in MAS; (b) a gene signature of cellular proliferation that localized to CD4+ and CD8+ T lymphocytes and NK cells marked by the expression of CD38 and HLA-DR, cells we term cycling lymphocytes; (c) greater expansion of CD38+HLA-DR+ T lymphocytes and NK cells in MAS compared with other pediatric inflammatory conditions, including MIS-C and viral infections; and (d) synergistic effects of IFN-I and IL-15 in driving the development of CD38+HLA-DR+ T lymphocytes in vitro. Here, CD4 is linked to macrophage activation syndrome.