Interaction between malignant T cells und murine cytokines via IFN-γ and IL-6. (A) Serum cytokine levels of murine and human IL-6, IL-5, and IFN-γ of vehicle- and ruxolitinib-treated mice with AITL and xenografts on treatment day 16 was determined using BD CBA Flex Sets with subsequent FACS analysis (n = 4 per group). (B) Scheme demonstrating the interaction of ITK-SYK⁺ CD4⁺ T cells with neutrophil granulocytes via IFN-γ and IL-6, also demonstrating the involvement of the different JAK/STATs. ITK-SYK leads to an activation of JAK1 and JAK3 kinases and subsequent activation of STAT3 and/or STAT6, either by direct phosphorylation or via other mediators, such as an activated TCR pathway. STAT3 and STAT6 then induce gene expression of various target genes, leading to cell activation, proliferation, migration into distant organs, and cytokine secretion. One of the secreted cytokines is IFN-γ, which activates the IFN-γ receptor on myeloid cells. This activates JAK1 and JAK2 to phosphorylate STAT1, thus inducing gene transcription, ultimately resulting in their recruitment to distant organs as well as their activation, proliferation, and cytokine secretion. IL-6 is such a secreted cytokines, which in turn can induce further T-cell activation, thus forming a positive feedback loop. (C,D) Expression of the IL-6 receptor and the IFN-γ2 receptor on CD4⁺ T cells and on granulocytes in control vs ITK-SYK⁺ mice. (E) IL-6 levels in the serum of healthy controls vs patients with TFH-PTCL/PTCL-NOS (n = 7; supplemental Table 3). (F) Survival of mice that had received transplantation with ITK-SYK⁺ TCL cells into C57Bl6 controls or IL-6 knockout mice (n = 6 per group). (G) Phenotypic score after 5 weeks of transplantation (WT vs IL-6 knockout mice). (H) Malignant ITK-SYK⁺ T cells in the PB or spleen of WT vs IL-6 knockout mice (n = 6 per group). Bars represent mean values with error bars showing the SEM. Statistical significance was calculated using the Student unpaired t test. ∗P < .05, ∗∗P < .01, ∗∗∗P < .001. hu, human.