STAT3 Gain-of-Function Mutations Underlie Deficiency in Human Nonclassical CD16 Monocytes and CD141 Dendritic Cells.

Genetic analysis of human inborn errors of immunity has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. The STAT family of transcription factors orchestrate hematopoietic cell differentiation. Patients with de novo activating mutations of present with multiorgan autoimmunity, lymphoproliferation, and recurrent infections. We conducted a detailed characterization of the blood monocyte and dendritic cell (DC) subsets in patients with gain-of-function (GOF) mutations across the gene. We found a selective deficiency in circulating nonclassical CD16 and intermediate CD16CD14 monocytes and a significant increase in the percentage of classical CD14 monocytes. This suggests a role for STAT3 in the transition of classical CD14 monocytes into the CD16 nonclassical subset. Developmentally, ex vivo-isolated STAT3 CD14 monocytes fail to differentiate into CD1a monocyte-derived DCs. Moreover, patients with STAT3 mutations display reduced circulating CD34 hematopoietic progenitors and frequency of myeloid DCs. Specifically, we observed a reduction in the CD141 DC population, with no difference in the frequencies of CD1c and plasmacytoid DCs. CD34 hematopoietic progenitor cells from patients were found to differentiate into CD1c DCs, but failed to differentiate into CD141 DCs indicating an intrinsic role for STAT3 in this process. STAT3-differentiated DCs produced lower amounts of CCL22 than healthy DCs, which could further explain some of the patient pathological phenotypes. Thus, our findings provide evidence that, in humans, STAT3 serves to regulate development and differentiation of nonclassical CD16 monocytes and a subset of myeloid DCs.