Lipopolysaccharide-Elicited TSLPR Expression Enriches a Functionally Discrete Subset of Human CD14+ CD1c+ Monocytes

Abstract

Thymic stromal lymphopoietin (TSLP) is a cytokine produced mainly by epithelial cells in response to inflammatory or microbial stimuli and binds to the TSLP receptor (TSLPR) complex, a heterodimer composed of TSLPR and IL-7 receptor α (CD127). TSLP activates multiple immune cell subsets expressing the TSLPR complex and plays a role in several models of disease. Although human monocytes express <i>TSLPR</i> and <i>CD127</i> mRNAs in response to the TLR4 agonist LPS, their responsiveness to TSLP is poorly defined. We demonstrate that TSLP enhances human CD14⁺ monocyte CCL17 production in response to LPS and IL-4. Surprisingly, only a subset of CD14⁺ CD16^- monocytes, TSLPR⁺ monocytes (TSLPR⁺ mono), expresses TSLPR complex upon LPS stimulation in an NF-κB- and p38-dependent manner. Phenotypic, functional, and transcriptomic analysis revealed specific features of TSLPR⁺ mono, including higher CCL17 and IL-10 production and increased expression of genes with important immune functions (i.e., <i>GAS6</i>, <i>ALOX15B</i>, <i>FCGR2B</i>, <i>LAIR1</i>). Strikingly, TSLPR⁺ mono express higher levels of the dendritic cell marker CD1c. This evidence led us to identify a subset of peripheral blood CD14⁺ CD1c⁺ cells that expresses the highest levels of TSLPR upon LPS stimulation. The translational relevance of these findings is highlighted by the higher expression of <i>TSLPR</i> and <i>CD127</i> mRNAs in monocytes isolated from patients with Gram-negative sepsis compared with healthy control subjects. Our results emphasize a phenotypic and functional heterogeneity in an apparently homogeneous population of human CD14⁺ CD16^- monocytes and prompt further ontogenetic and functional analysis of CD14⁺ CD1c⁺ and LPS-activated CD14⁺ CD1c⁺ TSLPR⁺ mono.