IL-17A inhibits the expansion of IL-17A-producing T cells in mice through "short-loop" inhibition via IL-17 receptor.
IL-23 and IL-17A regulate granulopoiesis through G-CSF, the main granulopoietic cytokine. IL-23 is secreted by activated macrophages and dendritic cells and promotes the expansion of three subsets of IL-17A-expressing neutrophil-regulatory T (Tn) cells; CD4(-)CD8(-)alphabeta(low), CD4(+)CD8(-)alphabeta(+) (Th17), and gammadelta(+) T cells. In this study, we investigate the effects of IL-17A on circulating neutrophil levels using IL-17R-deficient (Il17ra(-/-)) mice and Il17ra(-/-)Itgb2(-/-) mice that lack both IL-17R and all four beta(2) integrins. IL-17R deficiency conferred a reduction in neutrophil numbers and G-CSF levels, as did Ab blockade against IL-17A in wild-type mice. Bone marrow transplantation revealed that IL-17R expression on nonhemopoietic cells had the greatest effects on regulating blood neutrophil counts. Although circulating neutrophil numbers were reduced, IL-17A expression, secretion, and the number of IL-17A-producing Tn cells were elevated in Il17ra(-/-) and Il17ra(-/-)Itgb2(-/-) mice, suggesting a negative feedback effect through IL-17R. The negative regulation of IL-17A-producing T cells and IL-17A and IL-17F gene expression through the interactions of IL-17A or IL-17F with IL-17R was confirmed in splenocyte cultures in vitro. We conclude that IL-17A regulates blood neutrophil counts by inducing G-CSF production mainly in nonhemopoietic cells. IL-17A controls the expansion of IL-17A-producing Tn cell populations through IL-17R.
Smith
Emily
E
Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
Stark
Matthew A
MA
Zarbock
Alexander
A
Burcin
Tracy L
TL
Bruce
Anthony C
AC
Vaswani
Devin
D
Foley
Patricia
P
Ley
Klaus
K
D000818:Animals; D016764:Cell Polarity; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism*; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism*; D007958:Leukocyte Count; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*; D053722:Receptors, Interleukin-17 / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D020381:Interleukin-17; D053759:Interleukin-23; D053722:Receptors, Interleukin-17; D016179:Granulocyte Colony-Stimulating Factor