The Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway is critical in tuning immune responses and its dysregulation is tightly associated with cancer and immune disorders. Disruption of interleukin (IL)-15/STAT5 signaling pathway due to the loss of IL-15 receptor chains, JAK3 or STAT5 leads to immune deficiencies with natural killer (NK) cell abnormalities. JAK1, together with JAK3 transmits signals downstream of IL-15, but the exact contribution of JAK1 to NK cell biology remains to be elucidated. In this study we show that deletion of NK cell-intrinsic JAK1 leads to an almost complete loss of NK cells in the spleen, blood, and liver, proving a crucial role of JAK1 in peripheral NK cells. The absence of one allele of Jak1 suffices to drastically impair NK cell function whereas the deletion of JAK2 in NK cells has no impact on their survival or maturation. We thus propose that in contrast to currently used JAK1/JAK2 inhibitors, the use of JAK2-specific inhibitors would be advantageous for the cancer patients by leaving NK cells intact.
Publication in Frontiers in Immunology
Agnieszka Witalisz-Siepracka, Klara Klein, Daniela Prinz, Nicoletta Leidenfrost, Gernot Schabbauer, Alexander Dohnal and Veronika Sexl
Loss of JAK1 Drives Innate Immune Deficiency (2019), doi: 10.3389/fimmu.2018.03108