Human signal transducer and activator of transcription 5b (STAT5b) mutation causes dysregulated human natural killer cell maturation and impaired lytic function.

BACKGROUND:Patients with signal transducer and activator of transcription 5b deficiency have impairment in T-cell homeostasis and natural killer (NK) cells which leads to autoimmunity, recurrent infections, and combined immune deficiency. OBJECTIVE:In this study we characterized the NK cell defect in human NK cells, as well as Stat5b^-/- mice. METHODS:We used multiparametric flow cytometry, functional NK cell assays, microscopy, and a Stat5b^-/- mouse model to elucidate the effect of impaired and/or absent on NK cell development and function. RESULTS:This alteration generated a nonfunctional CD56^bright NK cell subset characterized by low cytokine production. The CD56^dim NK cell subset had decreased expression of perforin and CD16 and a greater frequency of cells expressing markers of immature NK cells. We observed low NK cell numbers and impaired NK cell maturation, suggesting that duanyu18135b is involved in terminal NK cell maturation in Stat5b^-/- mice. Furthermore, human duanyu18135b-deficient NK cells had low cytolytic capacity, and fixed-cell microscopy showed poor convergence of lytic granules. This was accompanied by decreased expression of costimulatory and activating receptors. Interestingly, granule convergence and cytolytic function were restored after IL-2 stimulation. CONCLUSIONS:Our results show that in addition to the impaired terminal maturation of NK cells, human duanyu18135b mutation leads to impairments in early activation events in NK cell lytic synapse formation. Our data provide further insight into NK cell defects caused by duanyu18135b deficiency.

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