CD8 T cell response to vaccinia following lymphopenia

描述（由申请人提供）：该提案重点关注T细胞的稳态增殖如何影响其产生抗病毒应答的能力。稳态增殖是一种机制，通过该机制，成熟幼稚T细胞响应于T细胞免疫缺陷而经历细胞分裂和明显转化为记忆细胞（“假记忆”T细胞）。虽然这一过程在隔离中得到了很好的研究，但其对能够对感染因子做出反应的记忆细胞的产生和维持的影响尚未研究。在这里，我们将研究如何CD 8 T细胞反应牛痘，痘病毒仍然用作疫苗的小痘，是受稳态增殖。这些假记忆T细胞的抗病毒应答将与初始T细胞和我们将通过有意接种产生的真实或“真正”记忆T细胞进行比较。TCR转基因T细胞的使用将允许我们比较这些不同分化状态的T细胞群体，但在每个群体上保持相同的TCR。有三个具体目标。在目标#1中，我们将确定已经经历稳态增殖的TCR转基因T细胞（假记忆T细胞）是否与真正的记忆T细胞相似或不同地应答。这将涉及测量T细胞存活、维持、病毒感染的刺激和有助于病毒清除的能力。在目标#2中，我们将解决假记忆T细胞的维持和/或反应性是否可以通过疫苗接种来增强（或削弱）。最后，在目标#3中，我们将颠倒实验系统并询问真正的记忆T细胞是否能够参与稳态增殖以及这些细胞是否保持其功能特性。

DESCRIPTION (provided by applicant): This proposal focuses on how homeostatic proliferation of T cells influences their capacity to make an anti-viral response. Homeostatic proliferation is a mechanism through which mature naive T cells undergo cell division and apparent conversion to memory cells ("pseudo-memory" T cells) in response to T cell immunodeficiency. While this process is well studied in isolation, its impact on the generation and maintenance of memory cells which can respond to infectious agents has not been studied. Here we will examine how CD8 T cell responses to Vaccinia, a pox virus still used as the vaccine for Small Pox, is influenced by homeostatic proliferation. The anti-viral response of these pseudo-memory T cells will be compared to both naive T cells and true or "bona fide" memory T cells which we will generate by deliberate vaccination. The use of TCR transgenic T cells will allow us to compare T cell populations in these various differentiation states, yet maintain the identical TCR on each population. There are three Specific Aims. In Aim #1, we will determine whether TCR transgenic T cells which have undergone homeostatic proliferation (pseudo-memory T cells) respond similarly or differently from bona fide memory T ceils. This will involve measurement of T cell survival, maintenance, stimulation by viral infection and ability to contribute to viral clearance. In Aim #2, we will address whether the maintenance and/or reactivity of pseudo-memory T cells can be enhanced (or impaired) by vaccination. Finally, in Aim #3, we will reverse the experimental system and ask whether bona fide memory T cells are able to participate in homeostatic proliferation and whether these ceils maintain their functional properties.