Interaction between phosphatidylserine and the phosphatidylserine receptor inhibits immune responses in vivo.
Phosphatidylserine (PS) on apoptotic cells promotes their uptake and induces anti-inflammatory responses in phagocytes, including TGF-beta release. Little is known regarding the effects of PS on adaptive immune responses. We therefore investigated the effects of PS-containing liposomes on immune responses in mice in vivo. PS liposomes specifically inhibited responses to Ags as determined by decreased draining lymph node tissue mass, with reduced numbers of total leukocytes and Ag-specific CD4(+) T cells. There was also a decrease in formation and size of germinal centers in spleen and lymph nodes, accompanied by decreased levels of Ag-specific IgG in blood. Many of these effects were mimicked by an agonistic Ab-specific for the PS receptor. TGF-beta appears to play a critical role in this inhibition, as the inhibitory effects of PS were reversed by in vivo administration of anti-TGF-beta Ab. PS-containing liposomes did not appear to directly inhibit dendritic cell maturation in vitro in response to a variety of stimuli, nor did it prevent their migration to regional lymph nodes in vivo, suggesting that the inhibitory effects may have resulted from complicated interactions between tissue cells and dendritic cells, subsequently inhibiting their ability to productively activate T lymphocytes.
Hoffmann
Peter R
PR
Department of Pediatrics, Program in Cell Biology, National Jewish Medical and Research Center, Denver, CO 80206, USA. peterh@pbrc.hawaii.edu
Kench
Jennifer A
JA
Vondracek
Andrea
A
Kruk
Ellen
E
Daleke
David L
DL
Jordan
Michael
M
Marrack
Philippa
P
Henson
Peter M
PM
Fadok
Valerie A
VA
D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D018858:Germinal Center / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006825:Hybridomas; D007106:Immune Sera / Q000008:administration & dosage / Q000097:blood; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000378:metabolism*; D007279:Injections, Subcutaneous; D008070:Lipopolysaccharides / Q000494:pharmacology; D008081:Liposomes; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010718:Phosphatidylserines / Q000008:administration & dosage / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013237:Stereoisomerism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology / Q000637:transplantation
C408982:CPG-oligonucleotide; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007106:Immune Sera; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D008081:Liposomes; D009838:Oligodeoxyribonucleotides; D010718:Phosphatidylserines; C498708:Ptdsr protein, mouse; D011956:Receptors, Cell Surface; C408123:phosphatidylserine receptor; D010047:Ovalbumin