Antigen dose and TCR repertoire in CD8+ T cell immunodominance hierarchies

CD8+或杀手T淋巴细胞(白血球)是免疫力的强者，在体内不断循环，以清除其他因癌症或感染病毒而具有危险的细胞。一个主要的困难是，杀伤T细胞也会施加选择性压力，导致病毒和肿瘤发生突变，从而避免免疫控制。这对于RNA病毒来说是一个特别严重的问题，因为它们在分裂时很容易发生变异。其中包括导致艾滋病的人类免疫缺陷病毒(HIV)，虽然流感病毒最重要的突变是那些改变抗体识别的病毒表面蛋白的突变，但这种T细胞逃逸突变也可能是流感的问题。人们对促进CD8+T细胞介导的流感免疫特别感兴趣的另一个原因是，杀手T细胞具有非常强的交叉反应。我们已经证明，启动小鼠CD8+T细胞以对抗目前在人类中传播的甲型流感病毒的疫苗接种方法，也将预防高度致命和危险的H5N1禽流感。目前的流感疫苗只刺激抗体，因此有兴趣进行重大重新设计的可能性。CD8+T细胞识别结合在我们自身移植尖端的病毒或肿瘤的微小元件(肽)，或I类主要组织相容性复合体(MHCI)分子。这些pMHCI复合体被称为表位。这里的重点是使用新的基因工程策略来找出，当病毒发生突变，破坏杀手T细胞看到的主要表位时，其他次要表位如何以促进有效免疫控制的方式被异常强调。随着我们用相对简单和安全的流感模型来研究这一点，我们将同时开发可能在艾滋病毒和肿瘤免疫方面有价值的策略。解决这一问题可能被证明是疫苗和免疫疗法方法设计方面的重大进步。

The CD8+, or killer , T lymphocytes (white blood cells) are the hit men of immunity, recirculating continually around the body to eliminate other cells that are dangerous because they are cancerous or infected with a virus. A major difficulty is that killer T cells also exert selective pressures that cause viruses and tumours to mutate and thus avoid immune control. This is a particularly serious problem for RNA viruses that readily mutate as they divide. These include the human immunodeficiency virus (HIV) that causes AIDS and, while the mutations that are most important with influenza viruses are those that modify viral surface proteins recognized by antibodies, such T cell escape mutants can also be a problem with influenza. The other reason why there is particular interest in promoting CD8+ T cell-mediated immunity to influenza is that the killer T cells are very cross-reactive. We have shown that vaccination approaches that prime mouse CD8+ T cells to resist influenza A viruses circulating currently in humans will also protect against the highly lethal, and dangerous H5N1 bird 'flu. The present flu vaccines only stimulate antibodies, so there is interest in the possibility of a major re-design. The CD8+ T cells recognize tiny elements (peptides) of the virus or tumour bound in the tip of our own transplantation, or class I major histocompatibility complex (MHCI) molecules. These pMHCI complexes are called epitopes. The focus here is on the use of novel genetic engineering strategies to find out how, when the virus mutates to disrupt the major epitopes seen by killer T cells, other minor epitopes can be abnormally emphasized in a way that promotes effective immune control. As we work on this with the relatively simple and safe influenza model we will concurrently develop strategies that may be of value in HIV and tumour immunity. Solving this problem could prove to be a substantial advance in the design of vaccines and immunotherapy approaches.