An IL-17F/A Heterodimer Protein Is Produced by Mouse Th17 Cells and Induces Airway Neutrophil Recruitment

Abstract

IL-17A and IL-17F are related homodimeric proteins of the IL-17 family produced by Th17 cells. In this study, we show that mouse Th17 cells also produce an IL-17F/A heterodimeric protein. Whereas naive CD4+ T cells differentiating toward the Th17 cell lineage expressed IL-17F/A in higher amounts than IL-17A/A homodimer and in lower amounts than IL-17F/F homodimer, differentiated Th17 cells expressed IL-17F/A in higher amounts than either homodimer. In vitro, IL-17F/A was more potent than IL-17F/F and less potent than IL-17A/A in regulating CXCL1 expression. Neutralization of IL-17F/A with an IL-17A-specific Ab, and not with an IL-17F-specific Ab, reduced the majority of IL-17F/A-induced CXCL1 expression. To study these cytokines in vivo, we established a Th17 cell adoptive transfer model characterized by increased neutrophilia in the airways. An IL-17A-specific Ab completely prevented Th17 cell-induced neutrophilia and CXCL5 expression, whereas Abs specific for IL-17F or IL-22, a cytokine also produced by Th17 cells, had no effects. Direct administration of mouse IL-17A/A or IL-17F/A, and not IL-17F/F or IL-22, into the airways significantly increased neutrophil and chemokine expression. Taken together, our data elucidate the regulation of IL-17F/A heterodimer expression by Th17 cells and demonstrate an in vivo function for this cytokine in airway neutrophilia.

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

“…Moreover, these γδ-T cells were producing IL-17 ( Fig. 2G), causing damage rather than tolerance as suggested previously (7,(17)(18)(19)(20).…”

Human RORγt + T H 17 cells preferentially differentiate from naive FOXP3 + Treg in the presence of lineage-specific polarizing factors

“…IL-17F is a proinflammatory cytokine with functions initially reported as similar to those of IL-17A and sharing the same receptor (45). Recent studies have revealed that IL-17A and IL-17F can be expressed as homo-or heterodimers that may bind IL-17 receptors with various affinities and may play not completely redundant functions (26,46,47). We found expression of IL-17F in only a fraction of IL-17A-secreting cells from NTreg, indicating the existence of distinct subpopulations that differentially express these cytokines and may be functionally distinct, an observation that warrants further investigation.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…There is a mutual interplay between neutrophils and CD4 + T helper 17 cells (Th17) [62]. While IL-17 and CXCL8 secreted by Th17 cells induce the recruitment of neutrophils, secretion of CCL2 and CCL20 by activated neutrophils attracts Th17 cells [61][62][63]. Th17 cells may further modulate neutrophil activity through secretion of TNFα, IFNγ and GM-CSF [62].…”