Hepatocyte Growth Factor (HGF) Favors Monocyte Differentiation into Interleukin (IL)-10+IL-12neg Regulatory Dendritic Cells.
Authors: Rutella Sergio , Bonanno Giuseppina , Procoli Annabella , Mariotti Andrea , Saulnier Nathalie , Curti Antonio , Leone Giuseppe , Lemoli Roberto M. 
Published: April 2020

Dendritic cells (DCs) are highly specialized antigen presenting cells (APCs) with unique capacity to fully activate and induce clonal expansion of naive and memory T cells. Recently, DCs have been implicated in the maintenance of antigen (Ag)-specific unresponsiveness or tolerance through the induction of regulatory T (Treg) cells. Several hematopoietic growth factors, including interleukin-10 (IL-10), transforming growth factor-β1 (TGF-β1) and granulocyte colony-stimulating factor (G-CSF), might promote the differentiation of regulatory dendritic cells (DCs) in vivo and/or in vitro. Hepatocyte growth factor (HGF) is a pleiotropic cytokine and its effects on human DC differentiation and function have not been investigated. Monocytes cultured with HGF (HGF-DCs) differentiated into accessory cells with DC features, released low amounts of IL-12p70 and up-regulated IL-10 both at the mRNA and at the protein level. HGF-DCs displayed a CD14+CD1a−costimulationlow phenotype, and expressed the inhibitory receptor ILT3. Upon activation with HGF-DCs, allogeneic CD4+CD25− T cells up-regulated CD25 and the Treg-associated transcription factor FoxP3, proliferated poorly and released high levels of IL-10 but trace amounts of IL-2 and IFN-≤ . Interestingly, blockade of surface ILT3 on HGF-DCs or neutralization of secreted IL-10 translated into partial restoration of T-cell proliferation. Addition of exogenous IL-2 to CD4+ T cells initially primed with HGF-DCs was not associated with the enhancement of T cell proliferation. Secondary stimulation of HGF-DC-primed CD4+ T cells with immunogenic DCs differentiated with GM-CSF and IL-4 from monocytes of the same donor resulted in optimal T-cell proliferation. Interestingly, HGF-DC-primed CD4+ T cells significantly inhibited the proliferation of naive CD4+CD25− T cells in a cell contact-dependent manner, as shown by co-culture experiments with transwell inserts.

Figure Figure

Finally, DNA microarray analysis revealed a unique gene expression profile of HGF-activated monocytes. Specifically, HGF-DCs over-expressed a set of 217 genes implicated in cellular metabolism, signal transduction, cell adhesion, cell-to-cell signaling, inflammation and immune response.

Genes up-regulated by HGF in freshly isolated monocytes are categorized according to their biological function Defense response 19 Cell adhesion and signaling 12 Signal transduction 32 Transcription regulation 17 Metabolism 35 Protein synthesis and degradation 24 Cytoskeletal organization 7 Transport 16 Chemotaxis 9 Cell proliferation and differentiation 6 Diverse physiological functions 9 Response to stress 9 Cell growth 4 Cell cycle 4 Morphogenesis 13 Unclassified 31

Of interest, HGF-DCs also upregulated mRNA signals for genes involved in tryptophan catabolisms, e.g., indoleamine 2,3-dioxygenase (IDO).

Collectively, our findings point to a novel role for HGF in the regulation of monocyte/DC functions. From a therapeutic standpoint, HGF might represent an attractive target for immunotherapy.