Melief Cornelis J M, Van Der Burg Sjoerd H, Toes Rene E M, Ossendorp Ferry, Offringa Rienk
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
Immunol Rev. 2002 Oct;188:177-82. doi: 10.1034/j.1600-065x.2002.18816.x.
In natural immune responses CD4+ T helper (Th) cells, reactive with peptide antigens presented by major histocompatibility complex (MHC) class II molecules on dendritic cells (DC), can drive the maturation of DC that is required for induction of CD8+ cytolytic T-lymphocyte (CTL) immunity. Proper induction, expansion and maintenance of CTL responses are achieved through delicate interactions between CD4+ T cells, DC and CD8+ T cells involving several ligand-receptor pairs. Th cells to a large extent operate through up-regulation of CD40L, which then interacts with CD40 on DC to cause DC maturation. Subsequent CTL induction by activated DC requires CD80/CD86 on the DC to interact with the CD28 costimulatory receptor on CD8+ T cells. For maintenance and full expansion of CTL, interaction of the DC-expressed 4-1BB ligand with its receptor 4-1BB on CTL is also important. Alternative molecular triggers of DC activation that can support induction of powerful CTL responses include agonistic anti-CD40 antibody or ligands of Toll-like receptors (TLR) such as LPS (TLR4 ligand) or oligodeoxynucleotides containing CpG-motifs (TLR9 ligand). The combination of CpG adjuvant with a 35 amino acid long synthetic peptide comprising both tumor-specific CTL and Th epitopes proved to be a highly effective vaccine formulation capable of inducing therapeutic immunity against human papillomavirus-induced mouse tumors. The recently acquired insights into antigen presentation and costimulatory signals have made possible the development of a new generation of therapeutic anticancer vaccines.
在天然免疫反应中，与树突状细胞（DC）上主要组织相容性复合体（MHC）II类分子呈递的肽抗原发生反应的CD4⁺辅助性T（Th）细胞，可驱动DC成熟，而DC成熟是诱导CD8⁺细胞毒性T淋巴细胞（CTL）免疫所必需的。通过涉及多个配体-受体对的CD4⁺T细胞、DC和CD8⁺T细胞之间的精细相互作用，可实现CTL反应的适当诱导、扩增和维持。Th细胞在很大程度上通过上调CD40L发挥作用，CD40L随后与DC上的CD40相互作用，导致DC成熟。活化的DC随后诱导CTL需要DC上的CD80/CD86与CD8⁺T细胞上的CD28共刺激受体相互作用。对于CTL的维持和充分扩增，DC表达的4-1BB配体与其在CTL上的受体4-1BB之间的相互作用也很重要。能够支持诱导强大CTL反应的DC激活的替代分子触发因素包括激动性抗CD40抗体或Toll样受体（TLR）的配体，如LPS（TLR4配体）或含CpG基序的寡脱氧核苷酸（TLR9配体）。事实证明，将CpG佐剂与包含肿瘤特异性CTL和Th表位的35个氨基酸长的合成肽相结合，是一种能够诱导针对人乳头瘤病毒诱导的小鼠肿瘤的治疗性免疫的高效疫苗制剂。最近在抗原呈递和共刺激信号方面获得的见解使得新一代治疗性抗癌疫苗的开发成为可能。
