Snyder James T, Alexander-Miller Martha A, Berzofskyl Jay A, Belyakov Igor M
Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Curr HIV Res. 2003 Jul;1(3):287-94. doi: 10.2174/1570162033485230.
CD8 CTLs are a major effector for protection against cancer as well as many infectious diseases, including HIV/AIDS. CD8 CTL recognize antigenic peptides in the context of class I MHC. CTL functional avidity has been shown to be an important determinant of in vivo efficacy. CTL that can recognize peptide/MHC only at high antigen density are termed low avidity CTL, while those that can recognize their cognate antigen at low densities are termed high avidity CTL. Recent studies have demonstrated that high avidity CTLs are essential for the effective clearance of viral infections and for the elimination of tumor cells. At this time, approaches that can target high avidity cells for expansion in vivo are not well defined; however, new insights are beginning to emerge. A recent study has shown that prime-boost immunization may be an effective method to generate high avidity CTLs that recognize HIV antigens. In addition, we recently found that high levels of costimulation (signal 2) can skew the CTL response toward higher avidity cells. Thus, vectors expressing a triad of costimulatory molecules (TRICOM) or dendritic cells expressing higher levels of costimulatory molecules, can be used to induce high avidity CTL. Finally a critical role for CD4+ T cell help in the generation of high avidity cells has recently been identified (Palmer, manuscript submitted). While high avidity CTLs are superior for viral and tumor clearance, they also have a greater sensitivity to antigen induced cell death. In some types of chronic infections, such as HIV and HCV, as well as in cancer, the host may lose, by clonal exhaustion or other apoptotic mechanisms, the effector cells that are most critical to viral or tumor clearance. In this review, we examine the current knowledge concerning CTL avidity. We discuss the factors that may distinguish high avidity CTLs from low avidity CTLs and describe some of the mechanisms these cells use to clear viral infections. In addition, we study possible immunization strategies that may be used to elicit higher avidity CTLs and describe what is known about the factors that render these cells more susceptible to apoptosis than low avidity CTLs. Finally, we will incorporate these various elements into a general discussion of possible approaches for induction and maintenance of an effective immune response that can result in clearance of tumors or chronic viral infections and the relevance to vaccine development.
CD8细胞毒性T淋巴细胞（CTL）是抵御癌症以及包括HIV/AIDS在内的许多传染病的主要效应细胞。CD8 CTL在I类主要组织相容性复合体（MHC）的背景下识别抗原肽。CTL的功能亲和力已被证明是体内疗效的重要决定因素。仅在高抗原密度下才能识别肽/MHC的CTL被称为低亲和力CTL，而那些在低密度下就能识别其同源抗原的CTL被称为高亲和力CTL。最近的研究表明，高亲和力CTL对于有效清除病毒感染和消除肿瘤细胞至关重要。目前，能够在体内靶向高亲和力细胞进行扩增的方法尚未明确；然而，新的见解正在开始出现。最近的一项研究表明，初免-加强免疫可能是产生识别HIV抗原的高亲和力CTL的有效方法。此外，我们最近发现高水平的共刺激（信号2）可以使CTL反应偏向更高亲和力的细胞。因此，表达三联共刺激分子（TRICOM）的载体或表达更高水平共刺激分子的树突状细胞可用于诱导高亲和力CTL。最后，最近已确定CD4 + T细胞辅助在产生高亲和力细胞中起关键作用（帕尔默，手稿待提交）。虽然高亲和力CTL在清除病毒和肿瘤方面更具优势，但它们对抗原诱导的细胞死亡也更敏感。在某些类型的慢性感染中，如HIV和HCV感染以及癌症中，宿主可能会通过克隆耗竭或其他凋亡机制失去对病毒或肿瘤清除最为关键的效应细胞。在本综述中，我们研究了有关CTL亲和力的现有知识。我们讨论了可能区分高亲和力CTL和低亲和力CTL的因素，并描述了这些细胞用于清除病毒感染的一些机制。此外，我们研究了可能用于引发更高亲和力CTL的免疫策略，并描述了已知的使这些细胞比低亲和力CTL更容易发生凋亡的因素。最后，我们将把这些不同的要素纳入关于诱导和维持有效免疫反应的可能方法的一般性讨论中，这种免疫反应可导致肿瘤清除或慢性病毒感染清除以及与疫苗开发的相关性。
