Boullart A C Inge, Aarntzen Erik H J G, Verdijk Pauline, Jacobs Joannes F M, Schuurhuis Danita H, Benitez-Ribas Daniel, Schreibelt Gerty, van de Rakt Mandy W M M, Scharenborg Nicole M, de Boer Annemiek, Kramer Matthijs, Figdor Carl G, Punt Cornelis J A, Adema Gosse J, de Vries I Jolanda M
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Science, Radboud University Nijmegen Medical Centre, P.O.Box 9101, 6500 HB Nijmegen, The Netherlands.
Cancer Immunol Immunother. 2008 Nov;57(11):1589-97. doi: 10.1007/s00262-008-0489-2. Epub 2008 Mar 6.
Dendritic cells (DC) are professional antigen-presenting cells of the immune system that play a key role in regulating T cell-based immunity. In vivo, the capacity of DC to activate T cells depends on their ability to migrate to the T cell areas of lymph nodes as well as on their maturation state. Depending on their cytokine-secreting profile, DC are able to skew the immune response in a specific direction. In particular, IL-12p70 producing DC drive T cells towards a T helper 1 type response. A serious disadvantage of current clinical grade ex vivo generated monocyte-derived DC is the poor IL-12p70 production. We have investigated the effects of Toll-like receptor (TLR)-mediated maturation on ex vivo generated human monocyte-derived DC. We demonstrate that in contrast to cytokine-matured DC, DC matured with poly(I:C) (TLR3 ligand) and/or R848 (TLR7/8 ligand) are able to produce vast amounts of IL-12p70, but exhibit a reduced migratory capacity. The addition of prostaglandin E2 (PGE2) improved the migratory capacity of TLR-ligand matured DC while maintaining their IL-12p70 production upon T cell encounter. We propose a novel clinical grade maturation protocol in which TLR ligands poly(I:C) and R848 are combined with PGE2 to generate DC with both high migratory capacity and IL-12p70 production upon T cell encounter.
树突状细胞（DC）是免疫系统中的专职抗原呈递细胞，在调节基于T细胞的免疫中起关键作用。在体内，DC激活T细胞的能力取决于它们迁移至淋巴结T细胞区域的能力以及它们的成熟状态。根据其细胞因子分泌谱，DC能够使免疫反应向特定方向倾斜。特别是，产生IL-12p70的DC促使T细胞向辅助性T细胞1型反应方向发展。当前临床级离体产生的单核细胞来源的DC的一个严重缺点是IL-12p70产生不足。我们研究了Toll样受体（TLR）介导的成熟对离体产生的人单核细胞来源的DC的影响。我们证明，与细胞因子成熟的DC相反，用聚肌苷酸-聚胞苷酸（poly(I:C)，TLR3配体）和/或R848（TLR7/8配体）成熟的DC能够产生大量的IL-12p70，但迁移能力降低。添加前列腺素E2（PGE2）可提高TLR配体成熟的DC的迁移能力，同时在与T细胞相遇时保持其IL-12p70的产生。我们提出了一种新的临床级成熟方案，其中TLR配体聚肌苷酸-聚胞苷酸和R848与PGE2联合使用，以产生在与T细胞相遇时具有高迁移能力和IL-12p70产生能力的DC。
