MD1 expression regulates development of regulatory T cells.
Intense interest has centered around the role of a subset of regulatory T cells, CD4+CD25+ Treg, in controlling the development of autoimmune disorders, allograft rejection, infection, malignancy, and allergy. We previously reported that MD1, a molecule known to be important in regulation of expression of RP105, also was important in regulating alloimmunity, and that blockade of expression of MD1 diminished graft rejection in vivo. One mechanism by which an MD1-RP105 complex exerts an effect on immune responses is through interference with an LPS-derived signal delivered through the CD14-MD-2-TLR4 complex. We show below that LPS signaling for Treg induction occurs at higher LPS thresholds that for effector T cell responses. In addition, blockade of MD1 functional activity in dendritic cells (using anti-MD1 mAbs, MD1 antisense deoxyoligonucleotides, or responder cells from mice with deletion of the MD1 gene), resulted in elevated Treg induction in response to allogeneic stimulation (in vivo or in vitro) in the presence of LPS. These data offer one mechanistic explanation for the augmented immunosuppression described following anti-MD1 treatment.
Gorczynski
Reginald M
RM
Departments of Surgery and Immunology, University Health Network and the Toronto Hospital, 200 Elizabeth Street, Toronto, Ontario, Canada. rgorczynski@uhnres.utoronto.ca
Kai
Yu
Y
Miyake
Kensuke
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology; D000954:Antigens, Surface / Q000096:biosynthesis* / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D006131:Growth Inhibitors / Q000502:physiology; D007519:Isoantigens / Q000502:physiology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000172:deficiency / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology; D016038:Skin Transplantation / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; C408982:CPG-oligonucleotide; D006131:Growth Inhibitors; D007519:Isoantigens; D008070:Lipopolysaccharides; C113553:Ly86 protein, mouse; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides