Induction of a gene expression program in dendritic cells with a cross-linking IgM antibody to the co-stimulatory molecule B7-DC.
While bivalent antibodies can block ligand-receptor interactions, IgM pentamers efficiently cross-link cell surface targets and evoke physiological responses. We have described one such interaction between an IgM antibody (Ab) and the B7-DC costimulatory molecule expressed by dendritic cells that induces strong antitumor immunity and modulates pathogenic responses associated with allergic asthma. Progressive changes in gene expression in dendritic cells activated by an IgM B7-DC cross-linking Ab resulted in the increased expression in 350 genes and decreased expression of more than 200 genes over the course of 24 h following Ab treatment. In particular, up-regulation of the caspase inhibitor FLIP and the chemokine receptor CCR7, and the down-regulation of the CXCR4 receptor provide a mechanistic basis of Ab-induced survival and enhanced migration into draining lymph nodes. Increased expression of both cell surface and secreted molecules known to be mediators of the immunomodulatory properties of dendritic cells was detected at both the levels of RNA and protein expression. This analysis documents the ability of IgM Ab to activate a gene expression cascade leading to important biological changes in cellular function and provides mechanistic insight into the potent immunomodulatory properties attributed to this Ab.
Blocki
Frank A
FA
Department of Immunology, Mayo Clinic, College of Medicine, 200 First St. S.W., Rochester, MN 55905, USA.
Radhakrishnan
Suresh
S
Van Keulen
Virginia P
VP
Heckman
Karin L
KL
Ciric
Bogoljub
B
Howe
Charles L
CL
Rodriguez
Moses
M
Kwon
Eugene
E
Pease
Larry R
LR
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D018122:B7-1 Antigen / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D017931:DNA Primers; D003712:Dendrites / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D061027:Programmed Cell Death 1 Ligand 2 Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D000906:Antibodies; D018122:B7-1 Antigen; D017931:DNA Primers; D007075:Immunoglobulin M; C556977:PDCD1LG2 protein, human; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein