Loss of JAK1 Drives Innate Immune Deficiency

Abstract

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. To study the consequences of JAK1 deficiency in NK cells, we generated mice with conditional deletion of JAK1 in NKp46+ cells (Jak1fl/flNcr1Cre). We show here that deletion of NK cell-intrinsic JAK1 significantly reduced NK cell numbers in the bone marrow and impaired their development. In line, we observed almost a complete loss of NK cells in the spleen, blood, and liver, proving a crucial role of JAK1 in peripheral NK cells. In line, Jak1fl/+Ncr1Cre mice showed significantly impaired NK cell-mediated tumor surveillance. Our data suggest that JAK2 is not able to compensate for the loss of JAK1 in NK cells. Importantly, conditional deletion of JAK2 in NKp46+ cells had no effect on peripheral NK cells revealing that NK cell-intrinsic JAK2 is dispensable for NK cell survival. In summary, we identified that loss of JAK1 in NK cells drives innate immune deficiency, whereas JAK2 deficiency leaves NK cell numbers and maturation unaltered. We thus propose that in contrast to currently used JAK1/JAK2 inhibitors, the use of JAK2-specific inhibitors would be advantageous for the patients by leaving NK cells intact.

STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity

“…Having established that IL-15/IL-15Rα treatment fully restores NK cell maturation but not NK cell effector functions in Stat1 β/β mice, we next tested whether NK cell functionality can be restored when NK cells mature in a STAT1-proficient environment. To enable functional assays in vivo, we made use of Jak1 fl/fl Ncr1Cre mice, which have strongly reduced NK cell numbers (32). We generated bone marrow chimeras by injecting WT, Stat1 −/− , or Stat1 β/β mixed with Jak1 fl/fl Ncr1Cre bone marrow cells or only Jak1 fl/fl Ncr1Cre bone marrow cells into irradiated Jak1 fl/fl Ncr1Cre mice and tested NK cell cytotoxicity using MHC I low target cells ( Figure 6F).…”

Whole Genome Sequencing of Spontaneously Occurring Rat Natural Killer Large Granular Lymphocyte Leukemia Identifies JAK1 Somatic Activating Mutation

“…Here we demonstrated that Jak1 Y1034C is a naturally occurring somatic mutation found in leukemic rats that was shown to elevate the phosphorylated levels of STAT1, STAT3 and STAT5. We observed the largest fold change of phosphorylated STAT5 by mutant relative to WT JAK1, suggesting STAT5 may be more readily phosphorylated by mutant JAK1 [42,44]. Mutation of JAK1 did not increase total JAK1 protein.…”

Molecular Regulation of NK Cell Maturation

“…The JAK-1/3-STAT5 pathway has been identified as being essential for NK cell maturation. Germ-line deletion of Jak1 or Stat5 and conditional deletion of Jak1 or Stat5 in NKp46 + cells both lead to a marked reduction in NK cell levels, as well as inhibition of NK cell maturation in the bone marrow and the periphery (16,67). Consistent with the reduced levels of mNK cells, Jak1 flox/flox Ncr1-iCre Tg or Stat5 flox/flox Ncr1-iCre Tg mice showed defective NK cell-dependent tumor surveillance.…”