Background/Purpose: T-helper (Th) cells actively communicate with adjacent cells by secreting soluble mediators, and yet crosstalk between Th cells and endothelial cells is poorly understood. Here, we demonstrated that the placental growth factor (PlGF), an angiogenic factor, was selectively secreted by Th17 cells, and promoted angiogenesis in vitro and in vivo.

Methods: Concentrations of PlGF and interleukin-17 (IL-17) in culture supernatants of stimulated T cells were measured using Enzyme-linked immunosorbent assay (ELISA). The angiogenic effect of PlGF produced by CD4⁺ T was assessed by measuring the tube formation, wounding migration, and chemotaxis of endothelial cells. Expression of Th17, Treg, and phospho Stat was analyzed by flow cytometry. Experimental Th17 disease model was induced in mice either by immunization with type II collagen (CII) or by injection of MOG_35-55 peptide.

Results: : ‘Angio-lymphokin’ PlGF, in turn, specifically induced Th17 cell differentiation and plasticity by activating STAT3 via binding to the FLT1 and NRP1 receptors and substituted for IL6 activity in IL-17 production, whereas it suppressed FOXP3⁺ Treg cell generation. The disruption of PlGF attenuated the severity of delayed-type hypersensitivity and experimental autoimmune encephalomyelitis in mice by reducing IL-17 production; the adoptive transfer of PlGF-overexpressing CD4⁺ T cells to these mice restored their disease phenotypes. On the contrary, selective overexpression of PlGF in T cells increased disease severity and IL-17 and STAT3 expressions in mice with autoimmune arthritis. Finally, we observed a correlation between concentrations of PlGF and IL17 in the synovial fluids of rheumatoid arthritis patients.

Conclusion:

Our findings provide novel insights into the PlGF-dictated links between angiogenesis, Th17 cell development, and autoimmunity, indicating that PlGF inhibitors could be used to control autoimmune and inflammatory diseases in hope of dual inhibition of angiogenesis and Th17 cell generation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/placental-growth-factor-regulates-the-generation-of-t-helper-17-cells-to-link-angiogenesis-with-autoimmunity/