Abstract
We previously showed that CD28 is expressed on human peripheral blood neutrophils and plays an important role in CXCR-1 expression and IL-8-induced neutrophil migration. In this work we demonstrate that Leishmania major infection of macrophages results in parasite dose-dependent IL-8 secretion in vitro and in IL-8-directed neutrophil migration, as blocked by both anti-IL-8 and anti-IL-8R Abs, toward the L. major-infected macrophages. In the neutrophil-macrophage cocultures, both CTLA4-Ig, a fusion protein that blocks CD28-CD80/CD86 interaction, and a neutralizing anti-IFN-gamma Ab inhibit the anti-leishmanial function of neutrophils, suggesting that the neutrophil-macrophage interaction via CD28-CD80/CD86 plays an important role in the IFN-gamma-dependent restriction of the parasite growth. Cross-linking of neutrophil-expressed CD28 by monoclonal anti-CD28 Ab or B7.1-Ig or B7.2-Ig results in phosphatidylinositol 3-kinase association with CD28 and in wortmannin-sensitive but cyclosporin A-resistant induction and secretion of IFN-gamma. Whereas the neutrophils secrete IFN-gamma with CD28 signal alone, the T cells do not secrete the cytokine in detectable amounts with the same signal. Thus, neutrophil-expressed CD28 modulates not only the granulocyte migration but also induction and secretion of IFN-gamma at the site of infection where it migrates from the circulation.
Publication types
-
Comparative Study
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Androstadienes / pharmacology
-
Animals
-
Antigens, CD / physiology
-
B7-1 Antigen / physiology*
-
B7-2 Antigen
-
CD28 Antigens / biosynthesis
-
CD28 Antigens / physiology*
-
Cell Communication / immunology
-
Cells, Cultured
-
Coculture Techniques
-
Cyclosporine / pharmacology
-
Dose-Response Relationship, Immunologic
-
Enzyme Inhibitors / pharmacology
-
Growth Inhibitors / immunology*
-
Growth Inhibitors / metabolism
-
Host-Parasite Interactions / immunology
-
Humans
-
Interferon-gamma / antagonists & inhibitors
-
Interferon-gamma / biosynthesis
-
Interferon-gamma / genetics
-
Interferon-gamma / metabolism*
-
Interleukin-8 / metabolism
-
Interleukin-8 / physiology
-
Leishmania major / growth & development*
-
Leishmania major / immunology
-
Macrophages / immunology*
-
Macrophages / metabolism
-
Macrophages / parasitology
-
Membrane Glycoproteins / physiology
-
Neutrophil Infiltration / immunology
-
Neutrophils / immunology*
-
Neutrophils / metabolism
-
Phosphatidylinositol 3-Kinases / physiology*
-
Phosphoinositide-3 Kinase Inhibitors
-
Signal Transduction / immunology
-
Transcription, Genetic / immunology
-
Wortmannin
Substances
-
Androstadienes
-
Antigens, CD
-
B7-1 Antigen
-
B7-2 Antigen
-
CD28 Antigens
-
CD86 protein, human
-
Enzyme Inhibitors
-
Growth Inhibitors
-
Interleukin-8
-
Membrane Glycoproteins
-
Phosphoinositide-3 Kinase Inhibitors
-
Interferon-gamma
-
Cyclosporine
-
Wortmannin