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      IRAK-M removal counteracts dendritic cell vaccine deficits in migration and longevity.

      The Journal of Immunology Author Choice
      Animals, Antigen Presentation, immunology, Blotting, Western, Cancer Vaccines, metabolism, Cell Proliferation, Cell Separation, Cell Survival, Chemotaxis, Leukocyte, Dendritic Cells, cytology, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Interleukin-1 Receptor-Associated Kinases, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL

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          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.

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