the p50 subunit of nf-κb orchestrates dendritic cell lifespan and activation of adaptive immunitynf-κb协调的p50亚基树突细胞寿命和激活适应性免疫.pdfVIP

The p50 Subunit of NF-kB Orchestrates Dendritic Cell Lifespan and Activation of Adaptive Immunity 1 2 2 1 2 3 Paola Larghi , Chiara Porta , Elena Riboldi , Maria Grazia Totaro , Lorenzo Carraro , Ciriana Orabona , Antonio Sica1,2* ` 1 Humanitas Clinical and Research Center, Rozzano, Milan, Italy, 2 Dipartimento di Scienze del Farmaco, Universita del Piemonte Orientale ‘‘A. Avogadro’’, Novara, Italy, ` 3 Department of Experimental Medicine and Biochemical Sciences, Universita di Perugia, Perugia, Italy Abstract Dendritic cells play a central role in keeping the balance between immunity and immune tolerance. A key factor in this equilibrium is the lifespan of DC, as its reduction restrains antigen availability leading to termination of immune responses. Here we show that lipopolysaccharide-driven DC maturation is paralleled by increased nuclear levels of p50 NF-kB, an event associated with DC apoptosis. Lack of p50 in murine DC promoted increased lifespan, enhanced level of maturation associated with increased expression of the proinflammatory cytokines IL-1, IL-18 and IFN-b, enhanced capacity of activating and expanding CD4+ and CD8+ T cells in vivo and decreased ability to induce differentiation of FoxP3+ regulatory T cells. In agreement, vaccination of melanoma-bearing mice with antigen-pulsed LPS-treated p502/ 2 BM-DC boosted antitumor immunity and inhibition of tumor growth. We propose that nuclear accumulation of the p50 NF-kB subunit in DC, as occurring during lipopo