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

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• STAT3 is crucial for hematopoietic cell differentiation and host defense.
• Gain-of-function (GOF) mutations in STAT3 cause severe immune dysregulation, including autoimmunity and recurrent infections.
• Understanding STAT3's role in specific immune cell subsets is vital for explaining disease pathogenesis.

Purpose of the Study:

• To investigate the impact of STAT3 GOF mutations on monocyte and dendritic cell (DC) subsets in patients.
• To characterize the developmental defects in monocytes and DCs caused by STAT3 GOF mutations.
• To elucidate the specific role of STAT3 in monocyte-to-DC differentiation.

Main Methods:

• Detailed immunophenotypic analysis of blood monocyte and DC subsets in patients with STAT3 GOF mutations.
• Ex vivo differentiation assays using patient-derived CD14+ monocytes and CD34+ hematopoietic progenitor cells.
• Quantification of cytokine production (CCL22) by differentiated DCs.

Main Results:

• STAT3 GOF mutations led to decreased nonclassical (CD16+) and intermediate monocytes, with increased classical (CD14+) monocytes.
• Ex vivo monocytes from patients failed to differentiate into CD1a+ monocyte-derived DCs.
• STAT3 GOF mutations reduced circulating CD34+ progenitors and myeloid DCs, particularly the CD141+ subset, with impaired differentiation into CD141+ DCs.
• STAT3 GOF-differentiated DCs produced less CCL22.

Conclusions:

• STAT3 plays a critical role in the development and differentiation of nonclassical monocytes and a subset of myeloid DCs in humans.
• STAT3 GOF mutations intrinsically impair the differentiation of CD34+ progenitors into CD141+ DCs.
• Defective monocyte and DC differentiation due to STAT3 GOF mutations likely contributes to the observed immunodeficiency and autoimmunity in patients.