Nature Biotechnology
- 24, 1581 - 1590 (2006)
Published online: 3 December 2006; | doi:10.1038/nbt1262
An essential role for Akt1 in dendritic cell function and tumor immunotherapyDongsu Park1, Natalia Lapteva2, Mamatha Seethammagari1, Kevin M Slawin2 & David M Spencer11
Department Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. 2
Scott Department of Urology, The Methodist Hospital, Houston, Texas 77030, USA.
Correspondence should be addressed to David M Spencer dspencer@bcm.edu Current dendritic cell (DC) vaccine preparations involving ex vivo differentiation and maturation produce short-lived, transiently active DCs that may curtail T-cell responses in vivo. We demonstrate that Akt1, downregulation of which decreases DC lifespan, is critical for proinflammatory signal–mediated DC survival and maturation. Lipopolysaccharide or CD40 signaling stabilizes Akt1, promoting both activation and Bcl-2–dependent survival of DCs. Expression of a potent allele encoding a lipid raft–targeted Akt1, MF- Akt, is sufficient for maturation and survival of murine bone marrow–derived DCs in vivo. MF-Akt–transduced DCs enhanced T-cell proliferation, activation and long-term memory responses, enabling eradication of large pre-established lymphomas and aggressive B16 melanomas. Human myeloid DCs expressing constitutively active MF-hAkt also survived significantly longer and promoted antigen-specific T-cell responses. Thus, Akt1 is a critical regulator of DC lifespan, and its manipulation in DCs can improve the clinical efficacy of DC-based tumor vaccines.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
