IRAK-M removal counteracts dendritic cell vaccine deficits in migration and longevity.
To function optimally as vaccines, dendritic cells (DCs) must actively migrate to lymphoid organs and maintain a viable, mature state for sufficient time to effectively present their Ag to cognate T cells. Unfortunately, mature DCs rapidly lose viability and function after injection, and only a minority leaves the vaccine site and migrates to lymph nodes. We show that all of these functions can be enhanced in DCs by removal of IL-1R-associated kinase M (IRAK-M). We found that IRAK-M is induced in DCs by TLR ligation and that its absence from these cells leads to increased activation of the p38-MAPK and NF-κB pathways, which, in turn, improves DC migration to lymph nodes, increases their longevity, and augments their secretion of Th1-skewing cytokines and chemokines. These biological effects have immunological consequences. IRAK-M(-/-) DCs increase the proliferation and activation of Ag-specific T cells, and a single vaccination with Ag-pulsed, LPS-matured IRAK-M(-/-) DCs eliminates established tumors and prolongs the survival of EG7 or B16.f10 tumor-bearing mice, without discernible induction of autoimmune disease. Thus, manipulation of IRAK-M levels can increase the potency of DC vaccines by enhancing their Ag-presenting function, migration, and longevity.
Turnis
Meghan E
ME
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
Song
Xiao-Tong
XT
Bear
Adham
A
Foster
Aaron E
AE
Gottschalk
Stephen
S
Brenner
Malcolm K
MK
Chen
Si-Yi
SY
Rooney
Cliona M
CM
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015153:Blotting, Western; D019496:Cancer Vaccines / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D002469:Cell Separation; D002470:Cell Survival / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
D019496:Cancer Vaccines; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
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