Human STAT5b mutation causes dysregulated human natural killer cell maturation and impaired lytic function

Abstract Background Patients with STAT5b deficiency have autoimmunity, recurrent infections and combined immune deficiency, which affects T-cell homeostasis and leads to natural killer (NK) cell impairment. Objective In this study, we characterized the NK cell defect in STAT5b-deficient human NK cells as well as Stat5b-/- mice. Methods We used multiparametric flow cytometry, functional NK cells assays, microscopy as well as a Stat5b-/- mouse model to elucidate the effect impaired and/or absent STAT5b has on NK cell development and function. Results This alteration generated a non-functional CD56bright NK cell subset, characterized by low cytokine production. The CD56dim NK cell subset had decreased expression of perforin and CD16 and a higher frequency of cells expressing markers of immature NK cells. We observed low NK cell numbers and impaired NK cell maturation suggesting that STAT5b is involved in terminal NK cell maturation in Stat5b-/- mice. Furthermore, human STAT5b-deficient NK cells had low cytolytic capacity, and fixed-cell microscopy showed poor convergence of lytic granules. This was accompanied by decreased expression of co-stimulatory and activating receptors. Interestingly, granule convergence and cytolytic function was restored after IL-2 stimulation. Conclusions Our results show that, in addition to the impaired terminal maturation of NK cells, human STAT5b mutation leads to impairments in early activation events in NK cell lytic synapse formation. Our data gives further insight into NK cell defects caused by STAT5b deficiency.