TY - JOUR
T1 - STAT3 Gain-of-Function Mutations Underlie Deficiency in Human Nonclassical CD16+ Monocytes and CD141+ Dendritic Cells
AU - Korenfeld, Daniel
AU - Roussak, Kate
AU - Dinkel, Sabrina
AU - Vogel, Tiphanie P.
AU - Pollack, Henry
AU - Levy, Joseph
AU - Leiding, Jennifer W.
AU - Milner, Joshua
AU - Cooper, Megan
AU - Klechevsky, Eynav
N1 - Funding Information:
This work was supported by funding from the Washington University School of Medicine in St. Louis Department of Pathology and Immunology, Siteman Cancer Center, the National Psoriasis Foundation (Translational Research Grant), and by National Institute of Biomedical Imaging and Bioengineering Grant 5R21EB024767-02, National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant 1R01AR075959-01, and National Cancer Institute Grant 1R01CA245277-01A1 to E.K.
Funding Information:
This work was supported by funding from the Washington University School of Medicine in St. Louis Department of Pathology and Immunology, Siteman Cancer Center, the National Psoriasis Foundation (Translational Research Grant), and by National Institute of Biomedical Imaging and Bioengineering Grant 5R21EB024767-02,
Publisher Copyright:
Copyright © 2021 by The American Association of Immunologists, Inc. All rights reserved.
PY - 2021/11/15
Y1 - 2021/11/15
N2 - 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 STAT3 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 CD16+CD14+ 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 vivoisolated STAT3GOF CD14+ monocytes fail to differentiate into CD1a+ monocyte-derived DCs. Moreover, patients with STAT3GOF 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. STAT3GOF-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.
AB - 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 STAT3 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 CD16+CD14+ 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 vivoisolated STAT3GOF CD14+ monocytes fail to differentiate into CD1a+ monocyte-derived DCs. Moreover, patients with STAT3GOF 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. STAT3GOF-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.
UR - http://www.scopus.com/inward/record.url?scp=85121944438&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.2000841
DO - 10.4049/jimmunol.2000841
M3 - Article
C2 - 34654687
AN - SCOPUS:85121944438
VL - 207
SP - 2423
EP - 2432
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 10
ER -